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ICBS 2018

Scientific Program

Towards Translational Impact

7th Annual ConferenceSeptember 24-27, 2018

Vancouver, Canada

www.chemical-biology.org


Towards Translational ImpactSeptember 24th – 27th, 2018 | Vancouver, BC

Local Program and Organizing CommitteeTom Pfeifer, Centre for Drug Research and DevelopmentMichel Roberge, University of British Columbia

Roger Linington, Simon Fraser UniversityNicolette Honson, Centre for Drug Research and Development

ICBS Organizing CommitteeHaian Fu, Chair, Emory University, USA Sally-Ann Poulsen, Griffith University, Australia Mahabir Gupta, University of Panama, Panama Masatoshi Hagiwara, Kyoto University, Japan Jason Micklefield, The University of Manchester, UK Siddhartha Roy, Bose Institute, India

Lixin Zhang, ECUST, China Jonathan Baell, Monash University, Australia Junying Yuan, Harvard Medical School, USA Petr Bartunek, CZ-OPENSCREEN and Institute of Molecular Genetics, Czech Republic

ICBS Young Chemical Biologist Award 2018 Selection CommitteeYimon Aye, Cornell University, USARatmir Derda, University of Alberta, CanadaEvripidis Gavathiotis, Albert Einstein College of Medicine, USAKenjiro Hanaoka, University of Tokyo, Japan

Christian Ottmann, Technische Universiteit Eindhoven, NetherlandsWilliam Pomerantz, University of Minnesota, USAQi Zhang, Fudan University, China

7th Annual Conference | September 24-27, 2018 | Vancouver, Canada

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Acknowledgements

Recording of sessions (oral or poster) by audio, video, or still photography is strictly prohibited except with the advance permission of the author(s) and the conference organizers.

Material contained in abstracts and presentations should be treated as personal communication and cited as such only with consent of the author(s).


Table of Contents

Author Index

Acknowledgements .....................................................2ICBS Board of Directors ..............................................4About ICBS .................................................................4ICBS International Advisory Board ...............................5Program at a Glance ....................................................6Welcome Letter ...........................................................9Program ....................................................................10

Thank you to our conference sponsors ......................16Keynote Speakers .....................................................17Presentations ............................................................19Rising Stars ...............................................................48Exhibitors ..................................................................52Poster Presenters ......................................................53Venue Map ................................................................55

A

Masahiko Ajiro ........................ 32Rima Al-awar .......................... 31Matthew Alteen ...................... 54Sebastian Andrei .................... 54Albert A. Antolin ...................... 25Heather Arnaiz ........................ 53Doug Auld .............................. 54

B

Anne Bang ............................. 37Jeremy M. Baskin ................... 29J.B. Brown ............................. 24

C

Robert Campbell .................... 45Michelle Chang ...................... 33Wansang Cho ......................... 53Michael Cohen ....................... 49

D

Phillip Danby ........................... 54

E

Joseph Egan .......................... 53Syusuke Egoshi ...................... 53

F

Victor Fadipe .......................... 54Eric S. Fischer ........................ 20Frederic Friscourt .................... 22

G

Thota Ganesh ......................... 54Thomas Garner ...................... 53Chloe Gerak ........................... 53Paul Guyett ............................. 37

H

Fred Haeckl ............................ 53Stephen J. Haggarty ............... 36Ting Han................................. 19Evan Haney ............................ 54Kenjiro Hanaoka ..................... 54Jason Hedges ........................ 54Stephanie Heinzlmeir .............. 54Nicole Houszka ...................... 53

I

Takayuki Ikeno ........................ 53Alena Istrate ........................... 53Andrey Ivanov ......................... 25

J

Namrata Jain .......................... 40Francois Jean ......................... 54Shireen Jozi ............................ 54

K

Akane Kawamura ................... 54Jennifer Kohler ...................... 21Milka Kostic ............................ 27Casey Krusemark ................... 31Karson Kump ......................... 53

L

Nicole LeGrow ........................ 53Jasmine Li-Brubacher ............. 53Dennis Liu .............................. 53Scott Lovell ............................ 28David Lupton .......................... 39

M

Dawei Ma ............................... 39Florian Mayerthaler ................. 34Guillaume Médard .................. 54James Meinig ......................... 53Poncho Meisenheimer ............ 46Jason Micklefield .................... 33Cameron Murray ..................... 54

N

Seyed Nasseri ........................ 53Ali Nejatie ............................... 53Sherry L Niessen .................... 42

P

Andrew J. Phillips ................... 43Sally-Ann Poulsen ................... 27Polina Prokofeva ..................... 54

Q

Kun Qian ................................ 54

R

Elena Reckzeh ........................ 53Anna Rutkowska-Klute ........... 54Katherine Ryan ....................... 34

S

Koichi Sasaki .......................... 54Shinichi Sato .......................... 40Saiko Shibata ......................... 53Eline Sijbesma ........................ 54Ellen M. Sletten ....................... 46Kimberly Snyder ..................... 38Mathieu Soetens .................... 53Barbara Sohr .......................... 53

T

Mirelle Takaki .......................... 54Lily Takeuchi ........................... 54Hong Yee Tan ......................... 53Masayasu Toyomoto ............... 54Michihiko Tsushima ................. 53

V

David Vocadlo ........................ 21

W

Chu Wang .............................. 49Shaomeng Wang .................... 19Amy Weeks ............................ 54Julian Wilke ............................ 53Michael Winzker ..................... 53Scott Wolkenberg ................... 30Jeffrey Y.K. Wong ................... 53Christina Woo ......................... 48

Y

Kenzo Yamatsugu .................. 53

Z

Charlotte Zammit .................... 53 Cristina Zamora ...................... 22Andrew Zhang ........................ 42Jin Zhang ............................... 45Y. George Zheng .................... 43

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ICBS Board of Directors

Lixin ZhangPresident (China)

Haian FuChair of Board (USA)

Jonathan BaellPresident Elect (Aus)

Rathnam ChaguturuTreasurer (USA)

Tom PfeiferSecretary (Can)

Masatoshi Hagiwara (Japan)

Zaneta Nikolovska-Coleska(USA)

Siddhartha Roy(India)

About ICBSThe International Chemical Biology Society (ICBS) is an independent, nonprofit organization dedicated to promoting research and educational opportunities at the interface of chemistry and biology. ICBS provides an important international forum that brings together cross-disciplinary scientists from academia, non profit organizations, government, and industry to communicate new research and help translate the power of chemical biology to advance human health.


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ICBS International Advisory Board

Stephen BenkovicPenn State

Sir Philip CohenUniversity of Dundee

Jian DingShanghai Institute of Materia Medica

Chris LipinskiMelior Discovery

Ferid MuradGeorge Washington University

Bernard MunosInnoThink

Litao ZhangBristol-Myers Squibb

Stuart SchreiberHarvard

Paul WorkmanICR-London

Tetsuo NaganoUniversity of Tokyo

Leonard ZonHHM/Harvard

Herbert WaldmannMax Planck Institute of Molecular Physiology

Junying YuanHarvard

ICBS 2018

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Program at a GlancePRECONFERENCE: MONDAY, SEPTEMBER 24, 2018

8:00AM – 6:00PM Meeting Registration Playhouse Lobby

8:30AM – 9:00AM Coffee Playhouse Lobby

9:00AM – 5:00PM Young Chemical Biologists’ Forum Orchestra Right & Left

9:00AM – 9:10AM Welcome Orchestra Right & Left

9:10AM – 11:10AM

Expert-Led Forum

9:10AM – 9:40AM Chemistry for Biologists Jonathan Baell, Monash University, Australia

9:40AM – 10:10AM Assay Development and Screening Doug Auld, Novartis Institute for Biomedical Research, USA

10:10AM – 10:40AM Structural Biology Scott Lovell, University of Kansas, USA

10:40AM – 11:10AM Insights for Chemical Biology in Industry Andrew Zhang, AstraZeneca, USA

11:10AM – 11:25AM Coffee Break Playhouse Lobby

11:25AM – 12:45PM Student-Led Forum, Presenters 1 through 5 Orchestra Right & Left

12:45 PM – 1:45PM Lunch on Your Own

1:45PM – 3:00PM Student-Led Forum, Presenters 6 through 10 Orchestra Right & Left

3:00PM – 3:30PM

Tech Talks Orchestra Right & Left

3:00PM – 3:15PMCreating and Deploying Next Generation Informatics Solutions – What We’ve Learned Along the Way Whitney Smith, Collaborative Drug Discovery, USA

3:15PM – 3:30PM Antibody-Drug Conjugates Graham Garnett, Zymeworks, Canada

3:30PM – 3:50PM Coffee Break and Exhibitor Viewing Salon A

3:50PM – 4:00 PM ICBS Conference Welcome Orchestra Right & Left

4:00PM – 4:05PM Keynote Introduction Orchestra Right & Left

4:05PM – 4:50PM Keynote – Craig M. Crews, Yale University, USAPROTAC-mediated Protein Degradation: Making Problem Proteins Go Away

Orchestra Right & Left

5:00PM – 8:00PM

ICBS Opening Reception and Young Chemical Biologists’ Social – Shark Club, Library RoomPlease join us for hors d’oeuvres and to network with your colleagues. CASH BAR is available

Off-Site | Shark Club


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CONFERENCE DAY 1: TUESDAY, SEPTEMBER 25, 2018



9:00AM – 9:15AM Welcome Orchestra Right & Left

9:15AM – 10:30PMSession I - DegradomicsChair: Shaomeng Wang


10:30AM – 10:50AM Coffee Break and Exhibitor Viewing Salon A

10:50AM – 12:10PMSession II – Glyco Chemical BiologyChair: David Vocadlo


12:15PM – 1:15PM Lunch on Your Own and Exhibitor Viewing Salon A

1:15PM – 1:55PM

Open Panel DiscussionChair: Rathnam Chaguturu, iDDPartners, USA

Academic/Industry Partnerships to Promote Drug Discovery Through Chemical Biology


1:55PM – 2:10PM Conference Updates Orchestra Right & Left

2:10PM – 3:15PMSession III – Computational Chemical BiologyChair: J.B. Brown



3:35PM – 4:55PMSession IV - Emerging and Other TopicsChair: Sally-Ann Poulsen


5:00PM – 7:00PMPoster Session on Balcony Level: Odd Numbered PresentationsPlease join us for hors d’oeuvres and to network with your colleagues. CASH BAR is available.

Balcony Level

CONFERENCE DAY 2: WEDNESDAY, SEPTEMBER 26, 2018



9:00AM – 9:05AM Conference Updates Orchestra Right & Left

9:05AM – 10:25AMSession V – The Chemical Biology – Medicinal Chemistry ContinuumChair: Yves Auberson



10:45AM – 12:15PMSession VI– Synthetic BiologyChair: Jason Micklefield


12:15PM – 1:15PM Lunch on Your Own and Exhibitor Viewing

1:15PM – 2:35PMSession VII – iPSC Chemical BiologyChair: Steve Haggarty


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2:35PM – 3:10 PM ICBS Business Meeting Orchestra Right & Left


3:40PM – 5:00PMRising Stars Chair: Haian Fu


5:00PM – 7:00PMPoster Session on Balcony Level: Even Numbered PresentationsPlease join us for hors d’oeuvres and to network with your colleagues. CASH BAR is Available

Balcony Level

CONFERENCE DAY 3: THURSDAY, SEPTEMBER 27, 2018



9:00AM – 09:05AM Conference Updates Orchestra Right & Left

9:05AM – 10:25AMSession VIII – Synthetic ChemistryChair: David Lupton



10:45AM – 10:50AM Keynote Introduction Orchestra Right & Left

10:50AM – 11:35AMKeynote - Jörn Piel, ETH Zurich, SwitzerlandNew Enzyme Tools From Uncharted Natural Product Space


11:35AM – 12:15PM

Open Panel SessionChair: Paul Clemons, Broad Institute, USA

Target Identification and Mechanism-of-Action Studies Using Chemical Biology



1:15PM – 2:45PMSession IX – Chemical Proteomics for Drug Target EngagementChairs: Michael Finley and Andrew Zhang


2:45PM – 3:00PM

Awards PresentationPoster Awards sponsored by ChemBridge and NovartisTravel Awards sponsored by Novartis, GlycoNet, STEMCELL Technologies and Beckman Coulter



3:20PM – 4:50PMSession X– Biosensors and ImagingChair: Jin Zhang


4:50PM – 5:00PM Closing Remarks Orchestra Right & Left


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Welcome LetterDear ICBS Members and Colleagues,

We are delighted to welcome you to the Seventh Annual Conference of the International Chemical Biology Society (ICBS) in the beautiful city of Vancouver.

Once again, this cross-disciplinary conference provides an opportunity and forum to bring together international leaders, field drivers, rising stars, trainees and contributors from across the global chemical biology community to share technological advances, exciting breakthroughs, and new information. It also provides a forum for creating new collaborations with colleagues from around the world, and to discuss the momentum of the field and our impact on society.

This year’s conference theme is Towards Translational Impact. Moving from the bench towards utility in the clinic, industry or environment; chemical biology has emerged as a powerful approach to provide proof of concept in model systems. It allows us to understand the relationship between target activity modulation by chemical compounds and phenotypic consequences, thus enabling the full potential of our discoveries. Chemical biology plays a special role in this translation by developing tools and methodologies to test and study the impact of these discoveries. As we listen to the fine line up of oral presentations and posters at ICBS2018, take a moment to rationalize the theories/hypotheses that each presenter is bringing to the table, as this may be the knowledge that one day may impact your translational research.

As always both young and established scientists will present at this meeting, providing a robust and interactive platform for all to learn, discuss and share throughout the course of the conference. The Rising Stars in Chemical Biology Awards Session will feature up-and-coming scientists in the field and will, as always, be a source of inspiration to all delegates. Overall, this conference will enable the ICBS community to further disseminate its scope and mission and to attract a growing number of members.

We are particularly proud of this year’s pre-conference Young Chemical Biologists’ Forum, a day organized for and by young researchers and trainees. For anyone new to the field, the day is intended to deepen their knowledge and expertise in different topics so as to enable innovative approaches to overcome the current and future challenges in chemical biology, resulting in mobilizing the next cohort of scientists. Thanks to the faculty and industry seminar presenters who volunteered to share their knowledge with our trainees.

Our thanks go to the members of the Organizing Committees who have worked hard to shape the program and invite speakers whose work is relevant and germane to our theme. We also wish to acknowledge Malachite Management Inc. who have kept us on a timeline to make sure this conference would happen, and provided numerous helpful tips and advice along the way. As always, special thanks go out to our Corporate Sponsors and Exhibitors for their generous support and without whom the conference would not be possible.

Thanks to the Keynote speakers, other invited speakers, oral and poster presenters who together comprise a program rich in content and variety.

Enjoy your stay in Vancouver, a city unlike any other. A city with beautiful nature sceneries, a city with unique mix of cultures, excellent food and energetic life style. We hope you will have wonderful time and we would like to invite you to attend next year’s ICBS conference planned for India in November, 2019!

Yours truly,

Tom Pfeifer, PhD, Centre for Drug Research and Development, Vancouver, BC, Canada

Zaneta Nikolovska-Coleska, MS, PhD, University of Michigan, Medical School, Ann Arbor, MI, USA

ICBS2018 Co-Chairs

ICBS 2018

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ProgramPRECONFERENCE: MONDAY, SEPTEMBER 24, 2018

8:00AM – 6:00PM Meeting Registration

8:30AM – 9:00AM Coffee

9:00AM – 5:00PM Young Chemical Biologists’ Forum

9:00AM – 9:10AM Welcome

9:10AM – 11:10AM Expert-Led Forum

9:10AM – 9:40AMChemistry for Biologists – Jonathan Baell, Monash University, AustraliaPAINS and Nuisance Compounds: Sorting the Wheat from the Chaff in Bioactive Compounds

9:40AM – 10:10AM Assay Development and Screening – Doug Auld, Novartis Institute for Biomedical Research, USA Considerations in the Design and Interpretation of Assays Applied to Drug Discovery

10:10AM – 10:40AMStructural Biology – Scott Lovell, University of Kansas, USAGene to Structure: Utilizing X-Ray Crystallography to Support Chemical Biology

10:40AM – 11:10AMInsights for Chemical Biology in Industry – Andrew Zhang, AstraZeneca, USAChemical Biology in Industry: Small Molecule Driven Target Deconvolution Strategies

11:10AM – 11:25AM Coffee Break

11:25AM – 12:45PM Student-Led Forum, Presenters 1 through 5

11:25AM – 11:40AMKun Qian, Emory University, USA Chemical Probe Discovery to Interrogate YAP-TEAD Interaction in The Hippo Signaling Pathway

11:40AM – 11:55AMEline Sijbesma, Eindhoven University of Technology, Netherlands Disulfide Trapping for the Identification of Selective PPI Stabilizers

11:55AM – 12:10PMAli Nejatie, Simon Fraser University, Canada Synthesis of Biological Probes

12:15AM – 12:30PMPhilip Danby, University of British Columbia, CanadaGlycosyl vs Allylic Cations in Spontaneous and Enzymatic Hydrolysis

12:30PM – 12:45PMMichael Winzker, Max Planck Institute of Molecular Physiology, GermanyProteolysis Targeting Chimera (PROTAC) – A New Tool in Drug Discovery

12:45 PM – 1:45PM Lunch on Your Own

1:45PM – 3:00PM Student-Led Forum, Presenters 6 through 10

1:45PM – 2:00 PMSebastian Andrei, Eindhoven University of Technology, Netherlands Rational Design of Semi-synthetic Natural Product 14-3-3 PPI Stabilizers

2:00PM – 2:15 PMKarson Kump, University of Michigan, USA Targeting Mcl-1 to Overcome Resistance in Solid Tumors

2:15PM – 2:30 PMOluwafemi Akintola, Simon Fraser University, Canada Allylic Carbasugars as Substrates for Glycoside Hydrolases

2:30PM – 2:45 PMElena Reckzeh, Max Planck Institute of Molecular Physiology, GermanyThermal Proteomic Profiling for Target Identification

2:45PM – 3:00 PMThomas Garner, Albert Einstein College of Medicine, USAAllosteric Modulation and Therapeutic Inhibition of Pro-Apoptotic BAX


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PRECONFERENCE: MONDAY, SEPTEMBER 24, 20183:00PM – 3:30PM Tech Talks

3:00PM – 3:15PMCreating and Deploying Next Generation Informatics Solutions – What We’ve Learned Along the Way Whitney Smith, Collaborative Drug Discovery, USA

3:15PM – 3:30PM Antibody-Drug Conjugates Graham Garnett, Zymeworks, Canada

3:30PM – 3:50PM Coffee Break and Exhibitor Viewing

3:50PM – 4:00 PM ICBS Conference Welcome

4:00PM – 4:05PM Keynote Introduction

4:05PM – 4:50PM Keynote - Craig M. Crews, Yale University, USAPROTAC-mediated Protein Degradation: Making Problem Proteins Go Away

5:00PM – 8:00PMICBS Opening Reception and Young Chemical Biologists’ Social – Shark Club, Library RoomPlease join us for a drink, hors d’oeuvres, and to network with your colleagues. A cash bar is available.

CONFERENCE DAY 1: TUESDAY, SEPTEMBER 25, 20188:00AM – 5:00PM Meeting Registration


9:00AM – 9:15AM Welcome

9:15AM – 10:30PMSession I - DegradomicsChair: Shaomeng Wang

9:15AM – 9:40AMShaomeng Wang, University of Michigan, USATargeting Gene Transcription by PROTAC

9:40AM – 10:15AMTing Han, National Institutes of Biological Sciences (NIBS), ChinaAnti-Cancer Sulfonamides Target Splicing by Inducing RBM39 Degradation Via Recruitment to the DCAF15 Ubiquitin Ligase Receptor

10:15AM – 10:30AMEric Fischer, Dana-Farber Cancer Institute, USAThalidomide Promotes Degradation of SALL4, a Transcription Factor Implicated in Duane Radial Ray Syndrome

10:30AM – 10:50AM Coffee Break and Exhibitor Viewing

10:50AM – 12:10PMSession II – Glyco Chemical BiologyChair: David Vocadlo

10:50AM – 11:15AMDavid Vocadlo, Simon Fraser University, CanadaDevelopment of Ultra-Sensitive Fret-Quenched Substrates for Quantitative Imaging of Glycoside Hydrolases in Living Cells

11:15AM – 11:40AMJennifer Kohler, University of Texas Southwestern Medical Center, USADiscovering Host Cell Receptors for Bacterial Toxins Using Photocrosslinking Sugars

11:40AM – 11:55AMFrederic Friscourt, University of Bordeaux, FranceSydnone-Modified Monosaccharides for the Metabolic Oligosaccharide Engineering of Living Cells

11:55AM – 12:10PMCristina Zamora, MIT, USAHuman Gut Microphysiological System Illuminates the Role of N-Glycans in Host-Pathogen Interactions of Campylobacter jejuni


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CONFERENCE DAY 1: TUESDAY, SEPTEMBER 25, 2018

1:15PM – 1:55PM

Open Panel DiscussionChair: Rathnam Chaguturu, iDDPartners, USA

Academic/Industry Partnerships to Promote Drug Discovery Through Chemical Biology

Panel: Doug Auld, Novartis USA, Scott Wolkenberg, Merck, Melvin Reichman, Lankenau Institute, Haian Fu, Emory University, Shaomeng Wang, University of Michigan, Rima Al-awar, Ontario Institute of Cancer Research, Yves Auberson, Novartis/EFMC Switzerland

1:55PM – 2:10PM Conference Updates

2:10PM – 3:15PMSession III – Computational Chemical BiologyChair: J.B. Brown

2:10PM – 2:35PMJ.B. Brown, Kyoto University, JapanActive Learning of Ligand-Target Interactions to Build Minimally Complex Yet Maximally Predictive Interaction Models

2:35PM – 3:00PMAlbert Antolin, Institute of Cancer Research, UKProbe Miner: Objective, Quantitative, Data-Driven Assessment of Chemical Probes

3:00PM – 3:15PMAndrey Ivanov, Emory University, USAIntegrated Computational and Experimental HTA Approaches to Discover and Target NSD3-Mediated Protein-Protein Interactions in Cancer


3:35PM – 4:55PMSession IV – Emerging and Other TopicsChair: Sally-Ann Poulsen

3:35PM – 4:00PMSally-Ann Poulsen, Griffith University, AustraliaDevelopment of Chemical Probes for Visualising DNA Synthesis in Complex Cellular Systems

4:00PM – 4:25PMMilka Kostic, Dana-Farber Cancer Institute, USAChemical Probes – Re-thinking our Ecosystem

4:25PM – 4:40PMScott Lovell, University of Kansas, USAStructure Guided Development of BfrB-Bfd Protein:Protein Interaction Inhibitors: a Novel Target for Antibiotic Development

4:40PM – 4:55PMJeremy Baskin, Cornell University, USAImpact: a Chemical Strategy for Imaging Phospholipase D and Phosphatidic Acid Signaling

5:00PM – 7:00PMPoster Session on Balcony Level: Odd Numbered PresentationsPlease join us for hors d’oeuvres and to network with your colleagues. A cash bar is available.

CONFERENCE DAY 2: WEDNESDAY, SEPTEMBER 26, 20188:00AM – 5:00PM Meeting Registration


9:00AM – 9:05AM Conference Updates


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9:05AM – 10:25AMSession V – The Chemical Biology – Medicinal Chemistry ContinuumChair: Yves Auberson

9:05AM – 9:30AMScott Wolkenberg, Merck, USAReducing Limitations in the Design of Photoaffinity Labeling Reagents: Development of a Diazirine-Compatible Cross Coupling Reaction

9:30AM – 9:55AMRima Al-awar, Ontario Institute for Cancer Research, CanadaDiscovery and Optimization of OICR9429, a WDR5 Chemical Probe

9:55AM – 10:10AMCasey Krusemark, Purdue University, USAIn Vitro Selection Assays: New Approaches and Applications in DNA-Encoded Libraries and Activity-Based Probes

10:10AM – 10:25AMMasahiko Ajiro, Kyoto University Graduate School of Medicine, JapanCDK9 Inhibitor FIT-039 Suppresses Viral Oncogenes E6 and E7 with a Therapeutic Effect for HPV-Induced Neoplasia


10:45AM – 12:15PMSession VI – Synthetic BiologyChair: Jason Micklefield

10:45AM – 11:10AMJason Micklefield, Manchester University, UKDiversification of Natural and Non-Natural Products Using Engineered Biosynthetic Pathways and Enzymes

11:10AM – 11:35AMMichelle Chang, University of California, Berkeley, USASynthetic Biology Approaches to New Fluorine Chemistry

11:35AM – 12:00PMKaity Ryan, University of British Columbia, CanadaBuilding Non-Proteinogenic Amino Acids

12:00PM – 12:15PMFlorian Mayerthaler, University of Münster, GermanyUnderstanding Conformational Changes in Nonribosomal Peptide Synthetases


1:15PM – 2:35PMSession VII – iPSC Chemical BiologyChair: Steve Haggarty

1:15PM – 1:40PMSteve Haggarty, Harvard University, USAHumanizing CNS Drug Discovery Using Patient-Specific Stem Cells Models

1:40PM – 2:05PMAnne Bang, Sanford Burnham Prebys Medical Discovery Institute, USAPhenotypic Screening of Human Induced Pluripotent Stem Cell Derived Neurons: Balancing Throughput With Relevance

2:05PM – 2:20 PMPaul Guyett, BrainXell, USAALS Drug Discovery Via High-Throughput Phenotypic Screening Using iPSC-Derived Human Motor Neurons

2:20PM – 2:35 PMKimberly Snyder, STEMCELL Technologies, CanadaChemical-Induction and Maintenance of Naïve-like Human Pluripotent Stem Cells

2:35PM – 3:10 PM ICBS Business Meeting

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CONFERENCE DAY 2: WEDNESDAY, SEPTEMBER 26, 20183:10PM – 3:40PM Coffee Break and Exhibitor Viewing

3:40PM – 5:00PM Rising Stars

3:40PM – 3:45PMRising Stars Session Introduction: ICBS Young Chemical Biologist Awards 2018Haian Fu, Chair of the Rising Star Selection Committee, Emory University, USA

3:45PM – 4:10PMRising Star 1Christina Woo, Harvard University, USAProximity-Directed O-GlcNAc Transferase for Protein-specific O-GlcNAcylation

4:10PM – 4:35PMRising Star 2Chu Wang, Peking University, ChinaChemoproteomics Profiling Reveals the Anti-Steatosis Mechanism of a Natural Flavonoid

4:35PM – 5:00PMRising Star 3Michael Cohen, Oregon Health and Science University, USADecoding Protein Adp-Ribosylation Networks in Cells Using Chemical Genetic Approaches

5:00PM – 7:00PMPoster Session on Balcony Level: Even Numbered PresentationsPlease join us for hors d’oeuvres and to network with your colleagues. A cash bar is available.

CONFERENCE DAY 3: THURSDAY, SEPTEMBER 27, 20188:00AM – 4:00PM Meeting Registration


9:00AM – 09:05AM Conference Updates

9:05AM – 10:25AMSession VIII – Synthetic ChemistryChair: David Lupton

9:05AM – 9:30AMDavid Lupton, Monash University, AustraliaNew Reactivity, New Structures...New Functions?

9:30AM – 9:55AMDawei Ma, Institute of Organic Chemistry, ChinaNew Strategies for Synthesizing Bioactive Alkaloids

9:55AM – 10:10AMShinichi Sato, Tokyo Institute of Technology, JapanDevelopment and Application of Tyrosine Click Reaction

10:10AM – 10:25AMNamrata Jain, University of British Columbia, Canada Synthesis and Application of a Mechanism-Based Inactivator of Endo-(Xylo)Glucanase


10:45AM – 10:50AM Keynote Introduction

10:50AM – 11:35AMKeynote - Jörn Piel, ETH Zurich, SwitzerlandNew Enzyme Tools From Uncharted Natural Product Space

11:35AM – 12:15PM

Open Panel SessionChair: Paul Clemons, Broad Institute, USA

Target Identification and Mechanism-of-Action Studies Using Chemical Biology

PanelMichael Finley, Janssen Research & Development, Bridget Wagner, Broad Institute, Andy Phillips, C4 Therapeutics, Scott Lovell, University of Kansas, Andrew Zhang, AstraZeneca


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CONFERENCE DAY 3: THURSDAY, SEPTEMBER 27, 201812:15PM – 1:15PM Lunch on Your Own and Exhibitor Viewing

1:15PM – 2:45PMSession IX – Chemical Proteomics for Drug Target EngagementChair: Michael Finley and Andrew Zhang

1:15PM – 1:40PMAndrew Zhang, AstraZeneca, USAElucidating PARP Inhibitor Selectivity Using a PARP Family Affinity Matrix

1:40PM – 2:05PMSherry Niessen, Pfizer, USAApplying Chemical Biology in the T790M-EGFR Program

2:05PM – 2:30PMAndy Philips, C4 Therapeutics , USATargeted Protein Degradation: Tools for Target Evaluation and Therapeutic Applications

2:30PM – 2:45PMY. George Zheng, University of Georgia, USABioorthogonal Chemical Probes to Interrogate Protein Acetylation

2:45PM – 3:00PM Poster and Other Awards


3:20PM – 4:50PMSession X – Biosensors and ImagingChair: Jin Zhang

3:20PM – 3:45PMJin Zhang, Univeristy of California, San Diego, USAA Suite of New Fluorescent Biosensors for Dynamic Visualization of Cell Signaling in Living Cells

3:45PM – 4:10PMRobert Campbell, University of Alberta, CanadaNew Colours and Applications of Genetically Encoded Biosensors to Probe Cell Signaling

4:10PM – 4:30PMEllen Sletten, University of California, Los Angeles, USAShortwave Infrared Fluorophores for Illuminating Biological Processes In Vivo

4:30PM – 4:50PMPoncho Meisenheimer, Promega, USASelectivity Differences Between Cellular and Biochemical Kinase Analysis

4:50PM – 5:00PM Closing Remarks

ICBS 2018

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Thank you to our conference sponsors


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Craig CrewsDr. Crews is the Lewis Cullman Professor of Molecular, Cellular and Developmental Biology and holds joint appointments in the departments of Chemistry and Pharmacology at Yale University. He graduated from the U.Virginia with a B.A. in Chemistry and received his Ph.D. from Harvard University in Biochemistry. Dr. Crews has a foothold in both the academic and biotech arenas; on the faculty at Yale since 1995, his laboratory pioneered the use of small molecules to control intracellular protein levels. In 2003, he co-founded Proteolix, whose proteasome inhibitor, Kyprolis™ received FDA approval for the treatment of multiple myeloma. Since Proteolix’s purchase by Onyx Pharmaceuticals in 2009, Dr. Crews has focused on a new ‘induced protein degradation’ drug development technology, PROTACs, which served as the founding IP for his latest New Haven-based biotech venture, Arvinas, LLC. Currently, Dr. Crews serves on several editorial boards and is an Editor of Cell Chemical Biology. In addition, he has received numerous awards and honors, including the 2013 CURE Entrepreneur of the Year Award, 2014 Ehrlich Award for Medicinal Chemistry, 2015 Yale Cancer Center Translational Research Prize, a NIH R35 Outstanding Investigator Award (2015) and the 2017 AACR Award for Outstanding Achievement in Chemistry in Cancer Research.

PROTAC-mediated Protein Degradation: Making Problem Proteins Go Away

Enzyme inhibition has proven to be a successful paradigm for pharmaceutical development, however, it has several

limitations. As an alternative, for the past 16 years, my lab has focused on developing Proteolysis Targeting Chimera

(PROTAC), a new ‘controlled proteolysis’ technology that overcomes the limitations of the current inhibitor pharmacological

paradigm. Based on an ‘Event-driven’ paradigm, PROTACs offer a novel, catalytic mechanism to irreversibly inhibit

protein function, namely, the intracellular destruction of target proteins. This approach employs heterobifunctional

molecules capable of recruiting target proteins to the cellular quality control machinery, thus leading to their degradation.

We have demonstrated the ability to degrade a wide variety of targets (kinases, transcription factors, epigenetic readers)

with PROTACs at picomolar concentrations. Moreover, the PROTAC technology has been demonstrated with multiple

E3 ubiquitin ligases, included pVHL and cereblon.

Keynote Speaker

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Jörn Piel Jörn Piel received a PhD in Chemistry at the University of Bonn, Germany, and conducted postdoctoral work with Bradley Moore and Heinz Floss at the University of Washington, Seattle. He then became Research Group Leader at the Max Planck Institute of Chemical Ecology in Jena, Germany, and Associate Professor of Bioorganic Chemistry at the University of Bonn. Since 2013 he is Full Professor of Microbiology at ETH Zurich. Research of his lab focuses on metabolic functions of “microbial dark matter”, the investigation and utilization of new biosynthetic enzymology, and ecology- and genome-based methods of natural product discovery.

New enzyme tools from uncharted natural product space

Most areas of the bacterial tree of life are functionally uncharacterized. These regions include numerous deep-branching

taxa that lack cultivated representatives and live in diverse habitats. Our lab uses metagenomic and single-cell-based

mining strategies to investigate whether this massive taxonomic and ecological diversity is a resource of metabolic novelty.

We have previously reported uncultured symbionts of marine sponges as a rich source of bioactive and biosynthetically

unusual compounds.1,2 The talk will present recent insights into the metabolic repertoire of ‘Entotheonella’ sponge

symbionts, a “talented” producer taxon with a rich and diverse chemistry comparable to that of streptomycetes. While

most of the biosynthetic pathways had no counterparts in known cultured bacteria, functional studies also revealed

mechanistically surprising enzymes that expand the chemical space of ribosomal peptide biosynthesis and have

widespread homologs in culturable prokaryotes.3-5 Implications for synthetic biology applications will be discussed.

[1] M. Wilson et al., Nature 2014, 506, 58.

[2] J.B. Cahn et al., Proc. Natl. Acad. Sci. U. S. A. 2018, 115, 1718.

[3] M. F. Freeman et al., Science 2012, 338, 387.

[4] M. F. Freeman et al., Nat. Chem. 2017, 9, 387.

[5] B .I. Morinaka et al., Science 2018, 359, 779.

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DegradomicsTargeting Gene Transcription by PROTAC

SHAOMENG WANGWarner-Lambert/Parke-Davis Professor in Medicine, University of Michigan, Ann Arbor, Michigan, USA

The proteolysis targeting chimera (PROTAC) strategy has emerged as a promising new approach for target validation and for the discovery of potential new therapeutics. In this lecture, I will present our recent efforts to target gene transcription by PROTAC. I will highlight the key differences between protein inhibitors and degraders, as well as the use of the PROTAC strategy to target those truly undruggable targets, including transcriptional factors.

Abstract Author Biography

Shaomeng Wang has been working on the discovery and development of novel small-molecules therapeutics for more than 20 years and is currently the Director of the Michigan Center for Therapeutic Innovation. His research focuses on targeting protein-protein interactions which regulate apoptosis and has resulted in the discovery and advancement of 6 compounds into Phase I/II clinical development targeting Bcl-2/Bcl-xL, MDM2 and IAP proteins. In more recent years, he has expanded his research program to target a number of PPIs, which regulate epigenetics, including histone readers, writers and erasers, and have advanced several classes of compounds into advanced preclinical development.

Dr Wang has co-founded four UM start-up companies to help bring drugs into clinical development and the marketplace; and has published >280 peer-reviewed papers and is an inventor of 50 issued US patents and international patents. He was elected as Fellow of the National Academy of Inventors in 2014 and is the 2014 University of Michigan Distinguished Innovator.

Anti-Cancer Sulfonamides Target Splicing by Inducing RBM39 Degradation via Recruitment to the DCAF15 Ubiquitin Ligase Receptor

TING HANNational Institute of Biological SciencesBeijing, China

Recent cancer genome sequencing efforts have identified mutations in pre-mRNA splicing factors and prompted active efforts to discover splicing inhibitors as a new strategy for treating cancer. Many of the proteins important for splicing, however, have no enzymatic activity and are thus challenging to inhibit via small molecules. We discovered that a class of clinically tested anti-cancer sulfonamides (collectively named as SPLicing inhibitor sulfonAMides (SPLAMs)) functions by promoting the interaction between the splicing factor RBM39 and the CUL4-DCAF15 E3 ubiquitin ligase, leading to polyubiquitination and proteasomal degradation of RBM39. Mutations in RBM39 reduce its interaction with CUL4-DCAF15, increase its stability and confer resistance to SPLAMs. RBM39 is essential for pre-mRNA splicing and inactivation of RBM39 by SPLAMs results in aberrant pre-mRNA splicing. Cancer cell lines originating from the hematopoietic and lymphoid lineages frequently exhibit sensitivity to SPLAMs, and their response to SPLAMs can be predicted by the expression levels of DCAF15. Taken together, our studies reveal RBM39-DCAF15 as the target of SPLAMs, and identify DCAF15 expression as a potential biomarker to guide clinical trials of SPLAMs.


Dr. Han received a BS degree at Tsinghua University in 2006 and a PhD degree at University of Michigan in 2013. He was a Life Sciences Research Foundation Fellow at UT Southwestern before joining NIBS, Beijing as an assistant investigator in 2017.

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ICBS 2018


Thalidomide Promotes Degradation of SALL4, a Transcription Factor Implicated in Duane Radial Ray Syndrome

ERIC S. FISCHERDana-Farber Cancer Institute/Harvard Medical SchoolBoston, United States

Frequently used to treat morning sickness, the drug thalidomide led to the birth of thousands of children with severe birth defects. Despite their teratogenicity, thalidomide and related IMiD drugs are now a mainstay of cancer treatment, however, the molecular basis underlying the pleiotropic biology and characteristic birth defects remains unknown. IMiDs exert their therapeutic effect by recruiting neo-substrates to the CRL4CRBN ubiquitin ligase, and hence provide clinical proof of concept for the rapidly emerging field of targeted protein degradation. Despite clinical success, and widespread use as PROTAC constituent, the full target repertoire of IMiDs remains elusive. Here we set out to establish the full repertoire of IMiD dependent substrates using a large scale proteomics approach.

Using multiplexed mass spectrometry-based proteomics, we conduct a large scale screen in a panel of cancer cell lines and human embryonic stem cells for targets of thalidomide, lenalidomide, pomalidomide, CC-885, CC-220, and a set of degrader/PROTAC molecules. Targets are validated using biochemical and cell biological tools.

We show that IMiDs disrupt a broad transcriptional network through induced degradation of multiple yet unknown C2H2zinc finger transcription factors, including SALL4, a member of the Spalt-like family of developmental transcription factors. Strikingly, heterozygous loss of function mutations in SALL4result in a human developmental condition that phenocopies thalidomide induced birth defects such as absence of thumbs, phocomelia, defects in ear and eye development, and congenital heart disease. We find that thalidomide induces degradation of SALL4 exclusively in humans, primates and rabbits, but not in rodents or fish.

Our study provides a first mechanistic link for the species-specific pathogenesis of thalidomide syndrome. Moreover, the surprising expansion in substrate repertoire for pomalidomide, suggest that IMiDs exhibit a large degree of polypharmacology contributing to both efficacy and adverse effects. In turn, the discovery that IMiDs target an unanticipated large set of C2H2zinc finger proteins with significant differences between thalidomide, lenalidomide, pomalidomide and CC-220, suggests that this chemical scaffold holds the potential to target one of the largest families of human transcription factors.


Eric Fischer, PhD, received his doctorate in biology from the University of Basel (Switzerland) in 2013. In 2015 Dr. Fischer joined the faculty of Harvard Medical School and the Dana-Farber Cancer Institute to continue his research using a multidisciplinary approach centered on structural biology, chemical biology, and proteomics. Research in his lab focusses on understanding the role that the post-translational modification with ubiquitin plays in cellular processes, development and disease, and the development of novel pharmacologic strategies targeting the ubiquitin machinery.

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Glyco Chemical Biology Development of Ultra-Sensitive Fret-Quenched Substrates for Quantitative Imaging of Glycoside Hydrolases in Living Cells

DAVID VOCADLOSimon Fraser UniversityBurnaby, Canada

Tunable Förster resonance energy transfer (FRET)-quenched substrates are useful for monitoring the activity of various enzymes within their relevant physiological environments. Development of FRET-quenched substrates for glycosidases, however, has been hindered by their constrained pocket-shaped active sites. The emerging relevance of this large class of enzymes in a range of human diseases is prompting increased interest in developing technologies to monitor glycosidases in cells and tissues. In this presentation we will discuss our recent progress in the design of substrates that overcomes this problem. Among these designs we will highlight the invention of Bis-Acetal-Based Substrates (BABS) that bear a hemiacetal aglycon leaving group that tethers fluorochromes in close proximity, also positioning them distant from the active site pocket. Following cleavage of the glycosidic bond, the liberated hemiacetal spontaneously breaks down, leading to separation of the fluorophore and quencher. The intact substrates show remarkably efficient quenching efficiency of greater than 99.5%. These dark to light substrates are efficiently turned over by various enzymes in vitro and kinetics experiments reveal that the first formed hemiacetal product rapidly breaks down, allowing monitoring of enzyme activity. Moreover, the various substrate designs we describe are also processed in living cells, enabling quantitative monitoring of glycosidase activity in their native environment. We expect this strategy to be broadly useful for the development of substrate probes for monitoring glycosidases, as well as a range of other enzymes having constrained pocket-shaped active sites.


Dr. David Vocadlo is a professor in the Departments of Chemistry and Molecular Biology and Biochemistry. He holds a Tier I Canada Research Chair in Chemical Biology at Simon Fraser University (SFU) where he is also Co-Director of the

Centre for High-Throughput Chemical Biology (HTCB) at SFU. He received his PhD from the University of British Columbia and was a postdoctoral fellow at UC Berkeley. Vocadlo joined SFU in 2004 where his team focuses on developing new chemical tools to improve our understanding of how carbohydrates influence cell function, with particular emphasis on their roles in neurodegenerative diseases. His pioneering research at the interface of chemistry and glycobiology spans fundamental research in enzymology through to translational preclinical animal studies. He and his team have been recognized with a number of national and international awards. His SFU research was cornerstone technology for co-founding of Alectos Therapeutics, which has since partnered with Merck to advance compounds to the clinic to combat neurodegenerative diseases.

Discovering Host Cell Receptors for Bacterial Toxins Using Photocrosslinking Sugars

JENNIFER KOHLER UT SouthwesternDallas, USA

Many pathogenic bacteria secrete protein toxins that recognize glycosylated receptors on the surface of host cells. While physiologically significant, the interactions between bacterial toxins and host glycoconjugates are often low affinity, and therefore difficult to characterize using traditional biochemistry methods.Methods : To solve this challenge, we developed photocrosslinking analogs of monosaccharides, including sialic acid and N-acetylglucosamine (GlcNAc), and developed strategies to incorporate these sugars into glycoconjugates of cultured mammalian cell lines.Results : Activation of the photocrosslinking functional group leads to covalent crosslinking with neighboring molecules. Crosslinked complexes can be isolated and analyzed by a variety of methods, including immunoblot and proteomics analysis.Conclusion : This approach can be used to covalently crosslink bacterial toxins to their host cell receptors, and more broadly to discover the interaction partners of glycosylated molecules. I will discuss strategies for incorporating photocrosslinking sugars into host cell glycoconjugates, as well as the application of these tools to define receptors for cholera and pertussis toxins.

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https://icbs2018.abstractcentral.com/admin?TAG_ACTION=GET_PERSON_DATA&XIK_PERSON_ID=xik_9abWcuJCeLiwyBvqgREwyNtV3tC4bmrs2idsK18hFEZc&NEXT_PAGE=PERSON_POP_UP

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Jennifer Kohler’s research group develops chemical biology methods to understand biological functions of glycosylated molecules. Methods include photocrosslinking sugar technology, which has been used to define glycan-mediated interactions.

Sydnone-Modified Monosaccharides for the Metabolic Oligosaccharide Engineering of Living Cells

FREDERIC FRISCOURTUniversity of Bordeaux - CNRS UM5287, European Institute of Chemistry and BiologyPessac, France

The bioorthogonal chemical reporter strategy, which elegantly combines the use of metabolically labeled azido sugars and 1,3-dipolar cycloadditions with strained alkynes, is emerging as a versatile technology for the labeling and visualization of glycans. Advantages of cyclooctyne-based probes encompass their high reactivity, non-toxicity (metal-free conditions) and synthetic modularity. However, azides have been shown to react, to varying degrees, with biological functionalities such as thiols. This inherent instability makes the azide functionality a precursor for the potential accumulation of secondary metabolites with unknown biological effects. In order to address this limitation, while keeping the advantages of the cyclooctyne framework as the reactive probe, we decided to investigate the utilization of other stable 1,3-dipoles as novel reporter.

In this context, we present herein the utilization of 3,4-disubstituted sydnones, a singular class of aromatic mesoionic dipoles, as novel chemical reporters for the metabolic oligosaccharide engineering (MOE) of living cells (Figure). By employing chemical and enzymatic strategies, the reporter was appended to various monosaccharides in order to study their metabolic invorporation into glycoconjugates in living mammalian cells.

Introduction of the sydnone moiety onto various metabolic monosaccharides demonstrated that not only its positioning on the sugar scaffold, but also on the class of carbohydrates, was of prime importance for a successful incorporation of the novel reporter into cell-surface glycoconjugates.

Due to its high biological stability and specific glycan incorporation, this novel chemical reporter will significantly expand our chemical biology toolbox for the visualization of labeled glycoconjugates.


After completing a PhD in chemistry in 2009 on asymmetric organometallic and organic catalysis with Prof. Pavel Kocovsky (University of Glasgow, UK), I transitioned to the field of Chemical Biology during my postdoctoral fellowship (2008-2014) in the laboratory of Professor Geert-Jan Boons at the Complex Carbohydrate Research Center (GA, USA), where I developed novel chemical probes for imaging the glycome in living cells. In 2014, I obtained a Junior Chair in Chemical Biology from the University of Bordeaux, France (INCIA lab, CNRS UMR 5287) and was recently recruited as a group leader at the European Institute of Chemistry and Biology (IECB) in Bordeaux. I recently received the prestigious CNRS-ATIP-Avenir award. My research focuses on using organic chemistry to develop novel selective tools that can probe the influence of glycans notably in healthy vs diseased states.

Human Gut Microphysiological System Illuminates the Role Of N-Glycans in Host-Pathogen Interactions of Campylobacter jejuni

CRISTINA ZAMORAMassachusetts Institute of Technology, USA

A human intestinal immune-competent micro-physiological system was employed to the study of NCTC 11168 Campylobacter jejuni pathogenicity, through the lens of its N-linked protein glycosylation (Pgl) pathway. The ability of this Gram-negative enteropathogen to infect and colonize the intestinal trats of avians and murine model organisms has been directly linked to the Pgl pathway, but the exact role of C. jejuni N-glycans in causing disease in humans is unclear.

To address this, an accessible tissue construct more closely resembling human intestinal epithelia was employed to characterize several changes in C. jejuni epithelial invasion, immunogenicity, and virulence factor composition and function. This tripartite co-culture of C2bbe1, HT29-MTX, and macrophage-derived mature dendritic cells, results in a mucin layer, intestinal epithelia and associated innate immune component.

Pgl knockout ΔpglE, lacking in cell-surface N-linked heptasaccharides, was found 100-fold less capable of adhering to and invading this intestinal model in cell infectivity assays.


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Chemokine and cytokine quantification by immunoassay revealed glyco-deficient strains ΔpglD and ΔpglE elicited decreased inflammation of the intestinal epithelium, but increased inflammation of the innate immune component of this tissue construct of up to 25-fold. Virulence-associated outer membrane vesicles produced by wildtype and ΔpglE 11168 C. jejuni were shown to have differential composition and function by activity-based protein profiling analysis, with wildtype vesicles able to rescue ΔpglE infectivity to wildtype levels in infection experiments.

Overall, use of this tripartite system allowed for further characterization of the multifaceted importance of the Pgl pathway in C. jejuni host-pathogen interactions within human intestinal contexts. We anticipate these methods will be broadly applicable to further studies of C. jejuni and to other enteropathogens of interest. This research was supported by the NIH (R01-GM097241 to B.I., R01EB021908 to L.G.G.) and DARPA (W911NF-12-2-0039 to L.G.G.).


Dr. Cristina Y. Zamora graduated from Boston College with a Bachelors of Science degree in Chemistry. In 2008, she started her graduate work in the Department of Chemistry at Tufts University in the lab of Prof. Krishna Kumar. At Tufts, Dr. Zamora developed novel fluorinated reagents for metabolic glycoengineering of cellular proteomes. She also biochemically characterized the activity and ligand preferences of several human sialidases, enzymes differentially regulated in diseases such as prostate cancer. In 2014, she joined the lab of Prof. Barbara Imperiali in the Department of Biology at MIT to characterize the relationship between the glycome of human pathogen Campylobacter jejuni and its infectivity in humans. From there, her research interests have broadened to targeted small molecule drug delivery, directed evolution and protein engineering, and alternative protein scaffold development.

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Computational Chemical BiologyActive Learning of Ligand-Target Interactions to Build Minimally Complex Yet Maximally Predictive Interaction Models

J.B. BROWNKyoto University Graduate School of MedicineKyoto, Japan

Automated chemical screening has ushered in an era which generates large ligand-target bioactivity matrices. As the size of the matrices have grown, they have become increasingly more challenging to manually assess, and the use of statistical pattern recognition (often called machine learning or currently “AI”) to analyze the matrices for patterns is becoming common. The recent explosion in interest in deeply-layered neural network architectures (“deep learning”) has generated the impression that “bigger means better”, but this leads to a problem in interpretation for chemical biology. Further, big data does not implicitly carry a guarantee of extra benefit. To investigate the opposite, that is - how small and simple a machine learning can be that is yet still predictive, we have developed the technique of ligand-target active learning.

We implement classification-type (yes/no) active learning by separating chemogenomic ligand-target Ki or IC50 bioactivity matrices into strong and weak pairs based on reasonable criteria. A human-intepretable machine learning algorithm known as the Random Forest employs an ensemble of decision trees to identify patterns that are rules for distinguishing between the strong and weak binders. The “active learning” terminology comes from the strategy of beginning with one strong and one weak binding pair each, iteratively adding one new ligand-target pair at a time, and subsequently re-updating the decision tree rules needed to separate the strong and weak binders. This is in constrast to the “full deck” dumping of all ligand-target bioactivities into a single, monolithic model.

Tested on GPCR, kinase, nuclear hormone receptor, and CYP450 families, the chemogenomic active learning methodology successfully builds highly predictive models of ligand-target bioactivity using only 5~20% of the original matrix of activities available. Further, it was tested in simulated prospective prediction experiments and found to demonstrate good performance. A convergence on predictive performance was found early on in most datasets, suggesting that the extent of predictability for a given chemical probe development project can be estimated efficiently from a reduced amount of existing activity data.

Active learning represents a novel way to efficiently develop novel chemical probes through use of feedback-driven, dynamic modeling and prediction processes that converge efficiently on the activity space of interest.


J.B. Brown was a post-bachelor researcher in diagnostic radiology at the US National Institutes of Health after completing BS degrees in computer science and math at the University of Evansville. His Ph.D. thesis on machine learning in chemoinformatics and bioinformatics was awarded from Kyoto University in 2010. After post-docs in computational biophysics and pharmacoinformatics, he became an assistant professor in the Department of Systems Onco-Informatics of the Kyoto University Graduate School of Medicine in 2014, and 18 months later, was awarded an independent position within the same graduate school, where he started the Life Science Informatics Research Unit. His research mixes chemoinformatics, clinical informatics, and medical bioinformatics, with an emphasis on translational research topics supported by core data processing and statistical methods. Notably, he has been researching methods in prediction of ligand-target interactions for a decade, and his recent “small data, simple model” methodologies and results in have received attention in news services such as AAAS’ EurkAlert and Japanese newspapers. His current research interests are in identification of small molecule modulators of immune response, and human-less fully automatic wet-dry bioactivity landscape exploration and knowledge extraction. J.B. is a member of the Japanese Society for Chemical Biology and the Chemical Society of Japan.


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Probe Miner: Objective, Quantitative, Data-Driven Assessment of Chemical Probes

ALBERT A. ANTOLINThe Institute of Cancer Research, London (UK)London, United Kingdom

Chemical probes are important widely-used reagents in chemical biology for understanding biological systems and for target validation. However, selection of chemical probes is largely subjective and prone to historical and commercial biases. Despite many publications discussing the aspirational properties of chemical probes and the proposal of ‘fitness factors’ to be considered when assessing chemical tools, scientists often select probes through web-based searchers or previous literature that are heavily biased towards older and often flawed probes our use vendor catalogues that do not discriminate between probes. Here, we analyse the scope and quality of published bioactive molecules and uncover large biases and limitations of chemical tools in public databases that need to be urgently addessed and should be always considered when using chemical tools. We also provide the online Probe Miner resource (http://probeminer.icr.ac.uk) capitalising on the plethora of public pharmacological data to enable quantitative, unbiased, objective, data-driven assessment of chemical probes and complement expert-curated approaches. We assess >1.8m compounds for their suitability as chemical tools against 2,220 human targets, demonstrating that large-scale public data can contribute to improve chemical probe assessment and prioritization to empower researchers in the selection of chemical tools for biomedical research and target validation.


Dr. Albert Antolin holds a BSc. and MSc. in Organic Chemistry from Ramon Llull University (Spain). After working as a molecular modeller in the pharmaceutical industry for two years (Laboratorios Salvat), Albert undertook a European PhD in Pharmacoinformatics at Pompeu Fabra University (Spain). Subsequently, Albert moved to The Institute of Cancer Research (London, UK) with a Marie Curie Tecniospring postdoctoral fellowship. Since 2017, Albert has been a Sir Henry Wellcome Fellow at the Institute of Cancer Research. His main lines of research include the application of computational methods to the development, characterisation and selection of chemical probes,

the understanding of drug (poly)pharmacology so that currently available drugs are better employed and the development safer and more efficacious anti-cancer therapeutics.

Integrated Computational and Experimental HTA Approaches to Discover and Target NSD3-Mediated Protein-Protein Interactions in Cancer

ANDREY IVANOVEmory UniversityAtlanta, United States

The recent advances in cancer genomics engaged with the expanded landscape of oncogenic protein-protein interaction (PPI) network have revealed the tumor heterogeneity and complexity of the oncogenic signaling. To enhance our understanding of cancer biology and discover novel therapeutic strategies, new effective chemical probes for oncogenic PPIs are urgently needed. Toward this goal we developed a highly robust high-throughput PPI screening platform and established a PPI network of cancer-associated proteins, termed OncoPPi. The OncoPPi links the cancer driver genes, both oncogenes and tumor suppressors and allows to identify new tumor dependencies to inform novel strategies for therapeutic interventions. As one example, the OncoPPi has revealed a new interaction between MYC oncogene and NSD3 protein, which plays a critical role in regulation of chromatin remodeling through a direct association with BRD4. Inhibition of interactions of NSD3 with MYC and BRD4 by small molecules would provide new tools to investigate the NSD3-dependent tumorigenesis, and will facilitate cancer drug development. Here we present a novel integrative platform to discover novel chemical probes for NSD3 signaling in cancer. It includes:

• Computational virtual screeing• Bioinformatics analysis of cancer genomics data• Protein-protein interaction screening• High-throuput fluorescence resonance energy transfer assay

We have developed and optimized a time-resolved fluorescence resonance energy transfer (TR-FRET) assay to monitor the interaction of NSD3 and MYC in miniaturized 1536-well ultra-high-throughput screening (uHTS) format. To identify compound scaffolds required for the efficient disruption of NSD3 PPIs, we have developed novel computational workflow that combines

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classical cheminformatics approaches with the large-scale cross-validation virtual screening methods. Based on the promising data from our pilot screening, we have launched a large-scale screening campaign to discover potent and selective inhibitors of NSD3 interactions.

Together, the OncoPPi network serves as a powerful resource to uncover new cancer vulnerabilities on oncogenic PPIs. OncoPPi Network has revealed new mechanism to control MYC-driven program through the protein-protein interaction with NSD3.The integration of our experimental and computational high-throughput approaches provides a robust platform to discover novel inhibitors of challenging PPIs to facilitate anti-cancer drug development.


Andrey A. Ivanov, Ph.D. is an Assistant Professor in the Department of Pharmacology and Emory Chemical Biology Discovery Center (ECBDC). He received his Masters degree in Chemistry from the Moscow State University, Department

of Chemistry, and his Ph.D. in Organic Chemistry and Computational Chemistry from Institute of Physiologically Active Compounds in Russia. Dr. Ivanov carried out his postdoctoral research at the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH working on medicinal chemistry and drug design for GPCRs. In 2011 he joined the Emory Chemical Biology Discovery Center and the Department of Pharmacology at Emory University and now he leads the Computational Chemical Biology and Systems Pharmacology team at the ECBDC. Dr. Ivanov is the recipient of NIH Fellows Award for Research Excellence, and the Emory University Research Committee Award, and Emory Winship Cancer Institute Fadlo R. Khuri Translational Research Award. He represents Emory University in the NCI Cancer Target Discovery and Development Network Data Harmonization and Informatics Portal Group (CTD2 D-HIP) and in the CTD2 Dashboard Working Group. Dr. Ivanov has authored or co-authored over 40 manuscripts and 3 book chapters. His group utilizes state-of-the-art bioinformatics, computational modeling, and systems biology approaches to understand molecular connections among biological pathways to facilitate drug target discovery and therapeutic development.

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Emerging and Other TopicsA Small Molecule Binder-Based Approach to Drug Discovery in Chemical Biology

SALLY-ANN POULSENGriffith University, Griffith Institute for Drug DiscoveryBrisbane, Australia

Fragment based drug discovery (FBDD) is a recently validated approach to identify small molecules as better chemical starting points for drug discovery. Since 2005, fragment screening has resulted in three FDA approved drugs and more than 30 drug candidates in clinical trials. The take-up of FBDD in academia, biotech and pharma is growing owing to this success.

Fragment screening is vastly different to high throughput screening (HTS), where hit compounds are relatively strong binders (KDs in the nM to µM range) commonly detected by functional output in a biochemical assay. In contrast, fragment screening is contingent on robust analytical methods to identify very weak protein−fragment binding interactions with KDs as low as mM. A number of biophysical techniques have been used to screen fragment libraries for small molecule binding partners for proteins. The most popular techniques to observe these binders include NMR, SPR and X-ray crystallography. The use of mass spectrometry for fragment screening has remained relatively underexplored. This presentation will highlight the attributes of mass spectrometry as a complementary screening method in fragment-based drug discovery. It will also identify the scope for applying this method to find small molecule binders that are functionally silent in classical assays.

REFERENCES[1] Woods, LA; Dolezal, O; Ren, B; Ryan, JH; Peat, TS; Poulsen, S-A. Native State Mass Spectrometry, Surface Plasmon Resonance, and X-ray Crystallography Correlate Strongly as a Fragment Screening Combination. J. Med. Chem. 2016, 59, 2192-2204.

[2] Chrysanthopoulos, P.K.; Mujumdar, P.; Woods, L.A.; Dolezal, O.; Ren, B.; Peat, T.S.; Poulsen, S.-A. Identification of a New Zinc Binding Chemotype by Fragment Screening. J. Med. Chem. 2017, 60, 7333-7349.


Sally-Ann Poulsen is Professor of chemistry and Senior Research Leader at Griffith Institute for Drug Discovery, Griffith University, Brisbane, Australia. Sally-Ann applies modern

chemistry approaches to harness the properties of small molecules as tools to address human disease. Her research goal is to discover new small molecules either as therapies (where current therapies are not available or are not effective) or as chemical probes (that further contribute to understanding complex biology) associated with cancer and infectious disease.

A significant outcome of her research has been the development of new small molecules as chemical probes that enable researchers to track and visualize DNA synthesis across complex mammalian and parasite systems – without chemical probes these systems are otherwise ‘invisible’ to researchers. The application of her novel pro-label methodology drew inspiration from the pro-drug:drug relationship of medicinal chemistry and constitutes a critical advance in chemical biology capability as it overcomes limitations of other probes, allowing greater applications in biology.

Sally-Ann has also developed and implemented native state mass spectrometry as an alternative and complementary enabling technology in drug discovery, specifically to advance the detection of small molecules that bind to proteins where detection has been challenging or not possible by mainstream technologies. Using this method she has discovered a novel inhibitor chemotype for an enzyme family that has been dominated for more than 70 years by one compound class of inhibitor.

Chemical Probes – Re-Thinking our Ecosystem

MILKA KOSTICDana-Farber Cancer InstituteBoston, United States

Chemical probes, tool compounds that can be used to interrogate intricate functional and mechanistic questions in biology, are one of the key contribution that chemical biology as a field continues to make to the broader life science and biomedical research communities. As such, chemical biologists have been investing resources and grass-roots efforts into defining what constitutes a chemical probe, and developing guidelines for characterization and validation. However, although standards have emerged, their wide adoption, implementation and

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enforcement are lagging behind. More importantly, in practice, many biologists continue to use “discredited” chemical probes, also known as historic compounds thus generating unreliable results and scientific conclusions. The talk will focus on some of the big picture questions surrounding chemical probes, their use and standards, and present some ways in which we can address current key challenges.


Milka Kostic, Ph.D. is the Program Director, Chemical Biology at Dana-Farber Cancer Institute, a Harvard Medical Schools affiliated hospital and research center in Boston, MA, USA. In this role, she supports a vibrant chemical biology program of about 120 scientists (faculty, postdocs, graduate students, staff scientists and technicians), who work tirelessly to develop chemistry-inspired research tools, platforms and strategies, to make new discoveries in basic biology, as well as translate these discoveries into improved clinical practice. Prior to Dana-Farber, Dr. Kostic was the Editor of Cell Chemical Biology and Structure for more than a decade, thus supporting and shaping chemical biology and structural biology communities. Dr. Kostic is a passionate advocate for chemical biology, and its transformative ability to accelerate basic and translational discoveries on the chemistry-biology-medicine continuum. She is also committed to career development and well-being of early career researchers, and promoting gender equality in science and society. She is an active blogger, and her main creative outlet is cooking and crafting plant-based meals for her friends and family!

Structure Guided Development of BfrB-Bfd Protein:Protein Interaction Inhibitors: a Novel Target for Antibiotic Development

SCOTT LOVELLUniversity of KansasLawrence, United States

The iron storage protein bacterioferritin (BfrB), present only in bacteria, functions to regulate iron concentrations by storing iron and releasing it as needed for metabolic functions. The BfrB structure consists of alpha helical subunits that dimerize and further assemble into a functional 24-mer (440 kDa) sphere-like structure that contains an 80 Å diameter core that can store up to 2,000 iron ions. BfrB is required for growth

of P. aeruginosa and release of iron is facilitated by a 7 kDa ferredoxin (Bfd). The structure of the BfrB-Bfd complex revealed a conserved protein-protein interface (PPI) poised for disruption of the protein-protein interaction by small molecules. We have developed small molecules that block the BfrB-Bfd interaction and disrupt iron homeostasis in P. aeruginosa thus providing a novel route for antibiotic development.

Structural information of protein:protein complexes can facilitate the development of lead compounds by providing details regarding specific molecular interactions at the atomic level. As such, the structure of the BfrB-Bfd complex was determined which permitted analysis of the PPI and the development of a training set of compounds that could potentially bind to the BfrB surface and inhibit its interaction with Bfd. Fragment-based drug design (FBDD) methods using STD-NMR were employed to identify initial compounds that 1) bind to BfrB and 2) target the PPI site. The compound binding mode was determined using X-ray crystallography and guided chemical modification of the initial fragment into larger compounds with higher binding affinity for BfrB.

The structure of the BfrB-Bfd complex revealed that 12 Bfd molecules bind to BfrB and provided mechanistic insight into iron transport from the BfrB core. Notably, the BfrB surface undergoes minimal conformational changes and accommodates specific Bfd residues. The initial fragment compound was found to bind BfrB with millimolar affinity at the PPI site. A new series of compounds, based on the initial fragment, were found to bind BfrB with low millimolar affinity and inhibited iron release from BfrB.

The structure of the BfrB-Bfd complex revealed a conserved PPI that permitted the development of compounds that block the protein-protein interaction. Initial compounds were identify using FBDD methods and were further expanded into more potent inhibitors that disrupt iron homeostasis in P. aeruginosa thereby providing a novel route for antibiotic development.


Dr. Scott Lovell has served as Director of the Protein Structure Laboratory (PSL) at the University of Kansas (KU) for the past decade and has 24 years of experience in the X-ray crystallography field. He received his Ph.D. from Purdue University in chemistry where he was trained in X-ray crystallography and studied the structural and optical properties of guest chromophores and biomolecules oriented in organic crystalline matrices. His postdoctoral work at the University of Wisconsin-Madison was focused on the structure determination of Tn5 transposase:DNA complexes in an effort to gain mechanistic insight regarding DNA transposition. Subsequently, he managed an industrial structural biology group at deCODE biostructures, located in the Chicago area, overseeing all aspects of gene-to-structure projects for external commercial clients and internal projects, focused on


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drug discovery and development. In addition he assisted in the maintenance and operation of a synchrotron beamline, operated by deCODE, at the Advanced Photon Source. As the Director of the PSL, his current laboratory collaborates with a diverse range of investigators from various academic and industrial institutions to obtain structural information of proteins using X-ray crystallography and utilizes high throughput techniques to rapidly move projects from gene-to-structure. As such, the PSL has completed over 250 protein crystal structures and coauthored 60 publications. Additionally, Dr. Lovell is a co-investigator on five NIH funded R01 grants aimed at inhibitor development and manages the structural biology work for these projects.

Impact: a Chemical Strategy for Imaging Phospholipase D and Phosphatidic Acid Signaling

JEREMY M. BASKINCornell UniversityIthaca, United States

Chemical imaging techniques have played instrumental roles in dissecting the spatiotemporal regulation of signal transduction pathways. Phospholipase D (PLD) enzymes affect cell signaling by producing the pleiotropic lipid second messenger phosphatidic acid via hydrolysis of phosphatidylcholine. It remains a mystery how this one lipid signal can cause such diverse physiological and pathological signaling outcomes, due in large part to a lack of suitable tools for visualizing the spatial and temporal dynamics of its production within cells.

Here, we report a chemical strategy for imaging phosphatidic acid synthesis by PLD enzymes in live cells. Our approach capitalizes upon the enzymatic promiscuity of PLDs, which we show can accept bioorthogonally tagged, or clickable, alcohols as reporters in a transphosphatidylation reaction. The resultant clickable lipids are then fluorescently tagged using an appropriate bioorthogonal/click chemistry reaction, enabling visualization of cellular membranes bearing active PLD enzymes.

This approach, which we have termed IMPACT (Imaging Phospholipase D Activity with Clickable Alcohols via Transphosphatidylation), has revealed pools of PLD activity at novel subcellular locations within individual cells and unexpected heterogeneity of PA signaling across cell populations. We are currently exploring and will present applications of IMPACT to elucidate novel mechanisms controlling PLD activation in normal physiology and in disease.

Collectively, our work highlights the importance of using chemical strategies to directly visualize, with high spatial and temporal resolution, the subset of signaling enzymes that are active.


Jeremy M. Baskin is the Nancy and Peter Meinig Family Investigator in the Life Sciences and Assistant Professor in the Department of Chemistry and Chemical Biology and the Weill Institute for Cell and Molecular Biology at Cornell University in Ithaca, New York. Born and raised in Montreal, Canada, Jeremy received an S.B. degree (Phi Beta Kappa) from the Massachusetts Institute of Technology in 2004, majoring in chemistry, minoring in biology and music, and performing research with Stephen Buchwald and Alice Ting. As an NSF and NDSEG predoctoral fellow with Carolyn Bertozzi at UC Berkeley, Jeremy developed copper-free click chemistry and applied it to image glycans in developing zebrafish, earning his Ph.D. in chemistry in 2009. Jeremy carried out postdoctoral research as a Jane Coffin Childs fellow with Pietro De Camilli at the Yale School of Medicine on the cell biology of phosphoinositide lipid metabolism, discovering that the mechanistic basis underlying a genetic disease featuring aberrant myelination is a defect in phosphoinositide biosynthesis at the plasma membrane. Jeremy’s independent research program at Cornell, established in 2015, centers on the chemical biology and cell biology of lipids and biological membranes. Using cross-disciplinary approaches, Jeremy’s lab pioneers advances in chemical approaches to elucidate novel signaling functions of lipid second messengers including phosphatidic acid and phosphoinositides. Jeremy’s work has been recognized by Beckman Young Investigator and NSF CAREER awards as well as his selection as part of the “Future of Biochemistry” special issue of Biochemistry.

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The Chemical Biology – Medicinal Chemistry ContinuumReducing Limitations in the Design of Photoaffinity Labeling Reagents: Development of a Diazirine-Compatible Cross Coupling Reaction

SCOTT WOLKENBERGMerck & Co., Inc.Kenilworth, Univted States

Diazirine-based photoaffinity labeling (PAL) reagents are an important class of chemical probes widely used to form stable covalent adducts with proximal binding partners in complex biological mixtures. Despite their prominence, diazirines have been synthesized only by a limited set of methods, imposing significant constraints on the design of diazirine-containing PAL probes. Convinced that available synthetic methods were compromising diazirine PAL probe design across a broad range of studies, we investigated expanding the range of methods for their incorporation.

Published diazirine PAL probes (n = 212) were analyzed according to reaction used for diazirine incorporation and category of diazirine placement in probe versus unlabeled parent pharmacophore. Despite the advantages of nesting diazirines in the active pharmacophore, this design is the least common found in the literature. And, surprisingly, we found a near absence of metal-catalyzed cross coupling reactions for diazirine PAL probe synthesis. Because biaryls are prominent in biologically-active compounds, this suggests synthetic access is a problem, and we investigated Pd-catalyzed cross coupling of diazirine-containing aryl halides and boronic acids to form biaryls, i.e. the Suzuki-Miyaura reaction (S-M).

We conducted 1) an initial fragment-based robustness screen to identify S-M conditions that give high cross-coupling efficiency while not degrading aryl diazirines followed by 2) a survey of pharmaceutically relevant substrates to define the scope and limitations of the method.

The robustness screen identified reaction conditions that gave good yields of S-M coupling product while minimally perturbing the diazirine reporter fragment. This is significant because diazirines themselves are reported as competent cross-coupling partners. The conditions were found to be highly scalable and exhibited broad scope when applied to a chemistry informer library of pharmaceutically relevant aryl boron pinacol esters. Furthermore, these conditions were used to synthesize a known diazirine-containing probe molecule with improved synthetic efficiency

Limited synthetic methods have constrained molecular design of PAL probes and results of labeling studies. A newly developed S-M protocol reduces these limitations and provides an alternative to published routes which rely on 3-4 step sequences and/or very long reaction times.


Scott Wolkenberg joined Merck Research Laboratories in West Point, PA, in 2003 and is currently Principal Scientist in the Chemical Biology group. Over the past 14 years, Scott and his teams have been involved in the design and synthesis of multiple compounds entering preclinical development including Kv1.5 blockers for atrial fibrillation, GlyT1 inhibitors for the treatment of cognitive disorders, and a PET imaging agent for early diagnosis of Alzheimer’s disease. Scott has been a project leader in the lead optimization space as well as the target validation and lead identification space. Scott has co-authored 43 peer-reviewed publications, is co-inventor on 20 patent applications, and has participated in and organized conferences in the US and abroad. He Chaired the 2015 Gordon Conference on High Throughput Chemistry and Chemical Biology. Scott was born and grew up in central New Jersey before attending Cornell University; he graduated in 1998 summa cum laude in chemistry with a double major in biology. He received a Ph.D. in organic chemistry from The Scripps Research Institute in La Jolla, CA, where he applied inverse-electron demand Diels-Alder reactions in total synthsis in the research group of Dale L. Boger.


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Discovery And Optimization of OICR9429, a WDR5 Chemical Probe

RIMA AL-AWAROntario Institute for Cancer ResearchToronto, Canada

At a fundamental level, gene expression is regulated by epigenetic histone modifications. Histone methyltransferases catalyze the transfer of the methyl group from S-adenosylmethionine to specific lysine residues on histones. Mixed lineage leukemia 1 (MLL1) is a methyltransferase that methylates lysine 4 on histone H3 (H3K4me3) and is an important regulator of the haemopoietic system. Dysregulation of MLL1 is often associated with acute myeloid and lymphoid leukemias, making it an attractive therapeutic target. WD40 repeat protein 5 (WDR5) is a component of the multiprotein MLL1 complex and is essential for its methyltransferase activity, and disruption of the WDR5/MLL1 interaction may therefore present a viable therapeutic option for the treatment of MLL-dependent leukemias. Employing a structure-based drug design approach, we have identified potent and orally bioavailable inhibitors of the WDR5/MLL interaction and demonstrated their efficacy in in vivo models.


Dr. Al-awar earned a PhD in synthetic organic chemistry from North Carolina State University and did a post-doctoral fellowship at the University of North Carolina at Chapel Hill prior to joining Eli Lilly and Company in 1995. In 2002, while still at Eli Lilly, Dr. Al-awar was promoted to Head in Discovery Chemistry Research and Technologies and later served as Head in Route Selection in Chemical Product Research and Development. In July 2008 she joined the Ontario Institute for Cancer Research (OICR) to build a drug discovery program. She is now the Director and Senior Principal Investigator of OICR’s Drug Discovery Program. Dr. Al-awar also serves as an Associate Professor in the Department of Pharmacology and Toxicology at University of Toronto.

In Vitro Selection Assays: New Approaches and Applications in DNA-Encoded Libraries and Activity-Based Probes

CASEY KRUSEMARKPurdue UniversityWest Lafayette, United States

The in vitro selection of encoded libraries allows a collective querying of function for many molecules simultaneously. Inspired by natural selection-driven evolution, the signal for this assay is DNA allele frequency change within a population in response to selective pressure. This approach has several advantages over assays employed in traditional small molecule screening campaigns, such as improved throughput and lower cost. We present an evaluation of in vitro selection assays with regard to their application to discovery from DNA-encoded libraries (DELs) and also to selection-based sensing, a new assay approach we have developed that uses DNA-linked probes to detect enzyme activity by DNA sequencing or quantitative PCR.

Selection assays included affinity purifications with immobilized proteins. Using the chromodomains of the chromobox (CBX) 7 and 8 proteins as a model system, we evaluated the robustness of affinity selections with a collection of DNA-linked ligands of known affinity and applied assays with DELs of peptidomimetics. Also, we developed selection approaches for enzyme substrates for protein kinase (protein kinase A, Src, e.g.), protease (caspase), and transferase (farnesyltransferase) activities. Crosslinking selections were developed where protein targets are covalently conjugated to proteins via an active site-labeling electrophile (fluorophosphonate) and implemented for detection of serine hydrolase activity.

Results indicated critical considerations for sucessful implementation of selection assays. These included minimization of background signal, absolute recovery of ligands and substrates, and overall enrichment values. With affinity selections, statistical analyses indicated low DNA tag bias and suggested that assays are sufficiently robust for both ligand discovery and for determination of quantitative structure-activity relationships. DEL selections yielded novel, selective ligands to CBX8. The development of substrate and crosslinking-based selections allowed a general approach for enzyme activity detection by DNA sequence analysis for the first time. Assays were implemented for detection of several activites in cell lysates and in a screen of 96 kinase inhibitors conducted by

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DNA sequencing.

In conclusion, this work highlights the potential of the in vitro selection assay both for ligand discovery in DELs and as a general enzyme assay platform.


Casey was born and raised in Pike County Illinois and received his B.S. degrees (Chemistry and Crop Science) from the University of Illinois-Urbana-Champaign. He obtained his Ph. D. in Biochemistry at the University of Wisconsin-Madison in the area of chemical biology under Peter Belshaw, with an emphasis on new chemical tools for mass spectrometry-based proteomics. He then conducted postdoctoral training at Stanford University with Pehr Harbury and Patrick Brown working on the directed evolution of synthetic chemicals. He began his independent career in 2013 at Purdue University in the Department of Medicinal Chemistry and Molecular Pharmacology. His group works on applications of DNA-encoded libraries for both novel ligand discovery and proteomic activity-based probes, with a focus on protein kinases and chromodomains. Outside of work, Casey enjoys gardening, basketball, his two young children, and cats.

CDK9 Inhibitor FIT-039 Suppresses Viral Oncogenes E6 and E7 with a Therapeutic Effect for HPV-Induced Neoplasia

MASAHIKO AJIROKyoto University Graduate School of MedicineKyoto, Japan

Cervical cancer is one of the leading causes of cancer deaths among women worldwide, and human papillomavirus (HPV) infection is the etiological cause in more than 95% of cases. HPV induces tumorigenesis through viral oncogenes, which depend on host cell factor cyclin-dependent kinase 9 (CDK9) for their transcriptional activation. The purpose of this study is to assesses the therapeutic effect of newly developed CDK9 inhibitor FIT-039 for cervical malignancy by targeting HPV viral gene expression and replication.

We examined FIT-039 for its effect on HPV gene expression in HPV+ cervical cancer cells. Primary keratinocytes monolayer and organotypic raft culture models were used to evaluate HPV viral replication and cervical intraepithelial neoplasia (CIN) phenotypes. Preclinical pharmacokinetics and toxicity tests for FIT-039 were also conducted. The anti-HPV effect of FIT-039 was further examined in vivo, using HPV+ cervical cancer xenografts.

FIT-039 inhibited HPV replication and expression of E6 and E7 viral oncogenes, restoring tumor suppressors p53 and pRb in HPV+ cervical cancer cells. The therapeutic effect of FIT-039 was demonstrated in CIN model of an organotypic raft culture, where FIT-039 suppressed HPV18-induced dysplasia/hyperproliferation with reduction in viral load. FIT-039 also repressed growth of HPV16+, but not HPV- cervical cancer xenografts without any significant adverse effects. Safety and pharmacokinetics of FIT-039 were confirmed for systemic and topical routes.

FIT-039 showed potent anti-HPV activity without significant toxicity in our preclinical studies. Thus, FIT-039 is expected to be a novel therapeutic for CIN to prevent cervical cancer. FIT-039 is currently evaluated in the phase I/IIa trial for anti-HPV activity in viral warts and further planned in CIN.


I graduated Tohoku University development of technology in 2005, and received MSc degree in the graduate school of life science in 2007. Then I moved to the Institute of Medical Science of the University of Tokyo, where I received PhD degree for the screening of a novel molecular target and evaluation of small molecule compounds for breast cancer. In 2010, I moved to the National Cancer Institute of NIH in the US as postdoctoral fellow, pursuing RNA biology for application to drug development. My studies there were focused on RNA splicing regulations associated with disease condition, viral infection, and drug resistance. In 2016, I joined to the Department of Drug Discovery Medicine of the Kyoto University as an assistant professor to lead a research group for development of small molecule compounds targeting viral infection and splicing-associated genetic diseases. My research goal is to provide a novel therapeutics for diseases currently without effective therapeutic options. In cooperation with Dr. Masatoshi Hagiwara, we demonstrated antiviral effect of CDK9 inhibitor FIT-039 against human papillomavirus (HPV), which is currently investigated in the phase I/IIa trial for HPV-induced viral warts.


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Synthetic BiologyDiversification of Natural and Non-Natural Products Using Engineered Biosynthetic Pathways and Enzymes

JASON MICKLEFIELDUniversity of ManchesterManchester, United Kingdom

Natural products often require further chemical modification, to improve their biological activities or physicochemical properties, for therapeutic and other applications. However, many of the most promising natural products, particularly the polyketides and nonribosomal peptides are highly complex molecules which offer limited opportunity for semi-synthesis, and are invariably inaccessible through total synthesis on the scale required for drug development. Consequently, alternative biosynthetic engineering approaches are required, which can enable the rapid structural diversification and optimisation of promising natural product scaffolds.

Synthetic biology, molecular genetics, enzymology and chemical biology methods are used.

In this lecture our recent progress in biosynthetic engineering will be presented. In addition methods for using enzymes from biosynthetic pathways to create non-natural products will be described.

New biosynthetic pathways to novel products will be presented.


Jason Micklefield is Professor of Chemical Biology within the School of Chemistry and the Manchester Institute of Biotechnology at the University of Manchester. He graduated from the University of Cambridge in 1993 with a PhD in Organic Chemistry and then moved to the University of Washington, USA, as a NATO fellow investigating various biosynthetic pathways and enzyme mechanisms. In 1995 he began his independent research career as a Lecturer in Organic Chemistry at Birkbeck College, University of London before moving to Manchester in 1998. Jason has made diverse contributions at the chemistry-biology interface in the areas of biocatalysis, enzyme mechanisms, biosynthesis, biosynthetic pathway engineering and development of RNA based regulatory tools (riboswitches).

Synthetic Biology Approaches to New Fluorine Chemistry

MICHELLE CHANG University of California, Berkeley, USA

The catalytic diversity of biological systems provides enormous potential for the use of living cells to provide new methods for organic and inorganic synthesis. One fundamentally interesting chemical phenotype is the ability of Streptomyces cattleya to catalyze the formation of C-F bonds. Because of the unique elemental properties of fluorine, site-selective fluorination has emerged as a powerful tool for improving the efficacy of small-molecule drugs. Our group is interested in using a synthetic biology approach to expand the scope of fluorinated natural products by engineering pathways for their production from the simple fluorinated building blocks provided by S. cattleya.


Michelle is a professor at UC Berkeley in the Departments of Chemistry and Molecular and Cell Biology. She received her Ph.D. from MIT, working with JoAnne Stubbe and Daniel Nocera, and her postdoctoral training with Jay Keasling at UC Berkeley. Her research group works at the interface of enzymology and synthetic biology, with a focus on studying biological fluorine chemistry, formation of mixed-valent nanomaterials by directional-sensing bacteria, and processes involved in developing synthetic biofuel and monomer pathways. She has received the Dreyfus New Faculty Award, TR35 Award, Beckman Young Investigator Award, NSF CAREER Award, Agilent Early Career Award, NIH New Innovator Award, DARPA Young Faculty Award, Camille Dreyfus Teacher-Scholar Award, 3M Young Faculty Award, Arthur Cope Scholar Award, and Pfizer Award in Enzyme Chemistry.

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Building Non-Proteinogenic Amino Acids

KATHERINE RYANThe University of British ColumbiaVancouver, Canada

There are hundreds of naturally occurring amino acids, the majority of which are not incorporated into proteins. Such non-proteinogenic amino acids have diverse structures and biological activities and could be used to make unnatural peptides. Here I will discuss my group’s work to elucidate biosynthetic pathways to non-proteinogenic amino acids.

In vitro reconstitution, mechanistic enzymology, and high-resolution protein X-ray crystallography

First, I will describe my group’s work on the pathway to L-piperazic acid, a non-proteinogenic amino acid containing a cyclic hydrazine that is incorporated into a variety of non-ribosomal peptides. We discovered that a heme-dependent enzyme catalyzes N-N bond formation to give L-piperazic acid from N-hydroxy-L-ornithine.1 Second, I will discuss our discovery of an enzyme pair that converts L-arginine to D-dehydroarginine in the pathway to the antibiotic indolmycin and highlight the key role of an O2-, pyridoxal phosphate-dependent oxidase.2 I will furthermore describe our high-resolution X-ray crystallography studies that allowed us to gather ‘snapshots’ during catalysis to understand how such PLP-dependent oxidases function.3

Across both projects, I will describe how we identified these enzymes, the in vitro work that allowed us to elucidate their functions, and the implications for our understanding of enzyme catalysis. Furthermore, I will describe potential applications of our work in biocatalyst development and drug discovery work.

REFERENCES:1Du YL, He HY, Higgins MA, Ryan KS (2017) A heme-dependent enzyme forms the nitrogen-nitrogen bond in piperazate. Nat. Chem. Biol. 13, 836-838.2Du YL, Singh R, Alkhalaf LM, Kuatsjah E, He HY, Eltis LD, Ryan KS (2016) A pyridoxal phosphate-dependent enzyme that oxidizes an unactivated carbon-carbon bond. Nat. Chem. Biol. 12, 194-199.3Hedges JB, Kuatsjah E, Du YL, Eltis LD, Ryan KS (2018) Snapshots of the catalytic cycle of an O2, pyridoxal phosphate-dependent hydroxylase. ACS Chem. Biol., 13, 965-974.


Katherine Ryan received her B.Sc. from the University of Chicago

in Biological Chemistry in 2002. She then carried out graduate studies at MIT, where she worked with Catherine Drennan to solve the X-ray crystal structures of natural product biosynthetic enzymes. From 2008-2010, was a postdoctoral fellow with Bradley Moore at the Scripps Institution of Oceanography at the University of California at San Diego. She became an Assistant Professor in the Department of Chemistry the University of British Columbia in 2011. Her group is interested in elucidating biosynthetic pathways to heterocycle-containing molecules and solving the structures of biosynthetic enzymes.

Understanding Conformational Changes in Nonribosomal Peptide Synthetases

FLORIAN MAYERTHALERUniversity of MünsterMünster, Germany

Nonribosomal peptide synthetases (NRPSs) are large modularly organized enzymes that synthesize a plethora of therapeutically important peptides. A module consists of multiple discrete domains that incorporate specifically one of over 530 different monomers through a sequence of coordinated reactions (1). During the catalytic cycle, the substrates are processed, covalently linked to the enzyme and then passed on to the next module. These diverse reactions necessitate that the domains undergo multiple conformational changes that are highly dynamic and still tightly regulated. Currently, little is known how the structural reconfigurations and interactions within and in-between domains are orchestrated (2). Initial studies have described the interaction between the peptidyl carrier protein (PCP) and the adenylation domain (3) but dynamic measurements that elucidate the regulation of the conformational changes have been missing. However, this knowledge is required to understand the coordination of the enzymatic cycle, and thus to precisely engineer NRPS for combinatorial biosynthesis of new products. In order to overcome this shortcoming we applied Förster Resonance Energy Transfer (FRET) spectroscopy to NRPS by either introducing the fluorophores genetically or using site-specific Michael-like addition with maleimides. This allowed us for the first time to monitor in real-time and in solution crucial interactions between substrates, the adenylation and the PCP domain (4). FRET is a known technique to study protein dynamics (5), but has not been applied to NRPS before due to their size and complexity. Here we report further studies on the dynamics of the domain alternation mechanism of


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the adenylation domain. Using pyrophospatase and different combinations of substrates, we can control the current state of the enzyme and the kinetics of the conformational changes and thereby study the directionality of NRPS. These investigations will foster our understanding of the NRPS machinery and, consequently, facilitate their bioengineering.

(1) S. Caboche et al., J. Bacteriol., 2010 (2) K. Weissman, Nat. Chem. Biol., 2015 (3) J. Zettler et al., FEBS J., 2010 (4) J. Alfermann et al., Nat. Chem. Biol., 2017 (5) T. Heyduk, Curr. Opin. Chem. Biol., 2002


Florian received his MSc in science from the University of Münster in organic chemistry and biochemistry. He has spent 4 months as a visiting scientist in the Department of Chemistry at Princeton, and at Bayer HealthCare. Florian is currently completing his PhD at the Institute of Biochemistry of the University of Münster in the lab of Dr. Henning Mootz where his research focuses on characterization of nonribosomal peptide synthetases.

Notes

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iPSC Chemical BiologyHumanizing CNS Drug Discovery Using Patient-Specific Stem Cells Models

STEPHEN J. HAGGARTYHarvard Medical School, Department of Neurology, Chemical Neurobiology Laboratory, Massachusetts General HospitalBoston, United States

Advances in a combination of disciplines—chemical biology, human stem cell biology, and human genetics—are impacting both our understanding of fundamental human disease biology and our ability to discover next-generation pharmacological agents targeting the root cause of disease. Perhaps nowhere are these advances most significant and critically needed than the area of central nervous system (CNS) disorders. While there has been an explosion of new genetic information revealing insight into their etiopathogenesis, major gaps exist in the translational of these observations to a deep understanding of the underlying disease biology, the discovery and validation of new targets for disease treatment or prevention, and improved diagnoses.

In this context, patient-derived, induced pluripotent stem cell (iPSC) models are increasingly recognized as providing robust and scalable ex vivo models systems of both rare and complex polygenic CNS disorders. Such ex vivo models of human disease, combined with powerful omic technologies, pathway-focused phenotypic screening, and high-content, quantitative imaging, enable systematic probing of the physiology and biochemistry of previously inaccessible cell types at specific stages of CNS development. Moreover, similar to other areas of medicine, recent findings suggest the value of a paradigm where therapies are first tested ex vivo for target engagement and disease-relevant functional signatures in patients’ cells to stratify patient populations prior to testing in vivo in formal clinical trials.

Here, I will provide select examples of programs within the Chemical Neurobiology Laboratory at Harvard Medical School/MGH seeking to characterize patient-specific iPSC models of neurodegenerative and neurodevelopmental disorders and identify targets for developing novel disease-modifying therapeutics. Specific examples of small-molecule screens will include efforts to probe mechanisms of neuroresiliency and proteostasis, as well as large-scale screens of neurogenesis

pathways. Continued expansion of a ‘living library’ of patient-specific iPSC models coupled to electronic health records and deep clinicopathological phenotyping along with further methodological optimization and development of improved disease-relevant, quantitative assays have the potential to advance multiple phases of novel target discovery and therapeutic development for CNS disorders.


Dr. Stephen J. Haggarty is an Associate Professor of Neurology at Harvard Medical School, an Associate Neuroscientist at Massachusetts General Hospital, and Director of the MGH Chemical Neurobiology Laboratory in the Center for Genomic Medicine. Dr. Haggarty is also a Senior Associate Member of the Broad Institute and Affiliate Faculty Member of the Harvard Stem Cell Institute. He completed his PhD in the Department of Chemistry & Chemical Biology at Harvard University, and joined the faculty of HMS/MGH in 2006. Dr. Haggarty was named the Stuart & Suzanne Steele MGH Research Scholar in 2017. Dr. Haggarty’s research program operates at the interface of neurology and psychiatry with a focus on dissecting the role of neuroplasticity and resiliency in health and disease. His efforts are guided by knowledge emerging from human genetics regarding the root causes of disease and have led to the discovery of novel chemical probes targeting the regulation of neurotrophic factor signaling, epigenetic regulation of neuronal gene expression, neurogenesis, synaptogenesis, and proteostasis networks. A major emphasis of his is the use of reprogramming technology to create patient-specific, induced pluripotent stem cells (iPSCs) as ex vivo models of neurogenetic disorders. The ability to differentiate human iPSCs into neural networks with the capacity to form synapses and regulate genes in an activity-dependent manner provides powerful new avenues for studies of neuroplasticity, for understanding the neurobiology of human disease, as well as for addressing the challenging goal of discovering novel targets and next-generation, disease-modifying therapies using the principles of genomic medicine.


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Phenotypic Screening of Human Induced Pluripotent Stem Cell Derived Neurons: Balancing Throughput With Relevance

ANNE BANGSanford Burnham Prebys Medical Discovery InstituteLa Jolla, United States

The lack of human-specific pre-clinical models of neurological disease is likely a factor that contributes to low rates of new therapies entering clinical trials. Human induced pluripotent stem cells (hiPSC) based models could potentially be used to address this void and aid in the development of clinically useful compounds. hiPSC are scalable, circumvent issues of species specificity, and allow interrogation of differentiated features of human neural cell-types not reflected by immortalized lines. Importantly, they can also carry disease traits in the context of specific human genetic backgrounds, offering an opportunity to better stratify patients and identify drug targets.

Development of technology platforms to interrogate hiPSC-derived neural cell types with relatively high-throughput will be advantageous not only for drug screening, but also for phenotype discovery, allowing testing of multiple patient derived lines, and variables, such as timing and dose response to therapeutic agents, pathway modulators, and stress inducers. Towards this goal, we have been working to develop platforms to assess fundamental aspects of neuronal morphology and physiology, providing a basis for further development of more complex phenotypic readouts and compound screens based on patient specific hiPSC-derived neurons. We will discuss a large-scale image based high-content compound screen of neuronal morphology. In addition, we will present our progress developing multi-electrode array (MEA) assays to monitor electrical activity, model synaptic plasticity, and evaluate drugs on networks of hiPSC-derived neurons.


Dr. Anne Bang joined the Sanford Burnham Prebys Medical Discovery Institute in June 2010 as Director of Cell Biology at the Conrad Prebys Center for Chemical Genomics, a state-of-the-art drug discovery center. Her current research efforts are directed at developing patient-specific, induced pluripotent stem cell (iPSC)-based disease models for drug discovery, with an emphasis on neurological and neuromuscular disease. Prior

to joining SBP she served as Director of Stem Cell Research at ViaCyte Inc, where she focused on developing stem cells as a source of pancreatic cells to treat diabetes. Dr. Bang received a B.S. from Stanford University, a Ph.D. in Biology from UCSD, and was a post-doctoral fellow at the Salk Institute.

ALS Drug Discovery Via High-Throughput Phenotypic Screening Using iPSC-Derived Human Motor Neurons

PAUL GUYETTBrainXell, Inc.Madison, United States

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily affecting motor neurons. Unfortunately, there are only two drugs approved to treat the condition, neither of which increases patient survival by more than a few months. This sobering reality highlights the urgent need for new ALS therapeutic development, which has been plagued by high failure rate of drug candidates during clinical trials. This high failure rate suggests that pre-clinical screening strategies need to be re-evaluated. One of the markers of disease in ALS patients is the aberrantly low expression of neurofilament light chain (NFL) in motor neurons. Further, recovery of NFL to normal levels prevents hallmark phenotypic changes in ALS neurons. Therefore, we wanted to establish a clinically relevant screening platform to identify compounds that return expression of NFL to normal levels in ALS patient derived motor neurons.

At BrainXell, we established new technologies to rapidly differentiate ALS patient induced pluripotent stem cells (iPSCs) into large quantities of neurons. We then used genome editing techniques to endogenously fuse NFL with a nanoluciferase (NLuc) reporter, thus enabling a high-throughput screening (HTS) system that monitors the expression levels of NFL after 72 h exposure to each compound. The assay was adapted to meet HTS requirements, including: large batch sizes, 1536-well format, minimal well-to-well variation, short-term culture, plating by automated dispenser, and low reagent volumes. Applying a quantitative HTS approach, we screened the LOPAC, NPC, and MIPE libraries (>6,000 compounds) in a dose dependent manner. Compounds that increase NFL expression by 50% (to approximately normal levels) were considered hits.

From these screens we identified 50 hit compounds that are

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currently going through secondary validation. Preliminary data looks promising. For example, one of these hits restores normal expression of NFL with no observed toxicity.

In conclusion, we have developed technologies to generate motor neurons from ALS patient iPSCs and demonstrated their application to increase clinical relevance of high-throughput drug discovery. Using this approach we can screen large libraries of small molecules to identify hit ALS therapeutics.


Paul Guyett is a Postdoctoral Scientist at BrainXell in Madison Wisconsin. He graduated from Washington State University in 2011 with a Ph.D. in Molecular Biosciences studying the biophysical contributions of hydrophobic amino acids to heterodimeric protein folding. Paul then worked with Kojo Mensa-Wilmot at University of Georgia using genetics and chemical biology to investigate protein kinase signaling pathways in the parasitic African Trypanosome. This work was then translated into a thriving academic drug discovery program. Paul was then recruited by BrainXell to progress their ALS drug discovery program. Paul’s interests are multidisciplinary, and center on the use of small-molecules to perturb biological systems as both scientific tools and potential therapeutics.

Chemical-induction and Maintenance of Naïve-Like Human Pluripotent Stem Cells

KIMBERLY SNYDERSTEMCELL Technologies Inc.Vancouver, Canada

Human pluripotent stem cells (hPSCs) are traditionally captured in a primed pluripotent state when isolated from early-stage embryos. Human naïve cells have been previously obtained by overexpression of transcription factors regulating key pathways controlling pluripotency. Here we demonstrate how the NaïveCult™-t2iLGö media system uses chemical inhibitors of histone acetyltransferases in combination with Wnt signalling modulators and small molecule inhibitors of mitogen-activated protein kinase kinase (MEK) and protein kinase C (PKC) to induce hPSCs to adopt a naive-like state. Further, this media system was developed to support the continuous robust expansion of naïve-like hPSCs.

Chemical generation of naïve hPSCs using NaïveCult™ Induction Kit involves sequential steps in which hPSCs, maintained in

mTeSR™1 or TeSR™-E8™, are first exposed to a histone deacetylase inhibitor and then subsequently transitioned and maintained in NaïveCult™ Expansion Medium. This process is carried out on hPSCs seeded on inactivated murine fibroblasts and under 5% oxygen conditions. Using our optimized protocol, we generated multiple naïve hPSC lines (n=5) from primed human embryonic stem cell lines Shef6, H1 and H9 and human induced pluripotent stem cells WLC-1C and STiPS-F016. We also tested the ability of naïve hPSCs maintained in NaïveCult™ Expansion Medium to differentiate into endoderm, mesoderm and ectoderm by using the STEMdiff™ Definitive Endoderm Kit, STEMdiff™ Mesodermal Induction Medium and STEMdiff™ Neural Induction Medium kits, respectively.

During the transition to naïve hPSCs, early passage colonies undergo robust morphological changes characterized by the acquisition of a domed phase-bright morphology on a background of heterogeneous cellular differentiation. By passage 5, cultures become increasingly homogenous with colonies typically demonstrating uniform domed and phase-bright morphology and low levels of background differentiation. Naïve hPSC lines, in addition to displaying a naïve cellular phenotype, also demonstrate the expected signature gene expression profiles associated with naïve pluripotency. Our results demonstrate that these cells are capable of differentiation to all somatic cell lineages with optimal results following a minimum of 21 days of re-priming in TeSR™-E8™ or mTeSR™1.

In summary, we have demonstrated robust establishment and expansion of chemically-induced and maintained naïve hPSCs using NaïveCult™ Induction Kit and Expansion Medium.


Kimberly Snyder obtained her Master of Science in Experimental Medicine at the University of British Columbia in 2014. She completed her studies under the supervision of Dr. Kelly McNagny studying the role of the CD34-related sialomucin, podocalyxin in metastatic breast cancer. Furthermore, in a collaboration with the Centre for Drug Research and Development (CDRD), She used pre-clinical mouse models to evaluate candidate therapeutic antibodies against podocalyxin to block the growth and metastasis of established tumors. In 2014, Kim was recruited to STEMCELL Technologies Inc. and is a Scientist in R&D working in the Pluripotent Stem Cell Biology Team. In her role, Kim primarily works on media development for the reversion and maintenance of primed human pluripotent stem cells to the naive-like state.


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Synthetic ChemistryNew Reactivity, New Structures...New Functions?

DAVID LUPTONMonash UniversityMelbourne, Australia

Discoveries in chemical synthesis often provide access to new materials, or previously inaccessible due to inefficiencies in chemical synthesis. This pipeline, connecting novel molecular structures to discoveries in application focused chemistry, will remain integral in the future as increasingly challenging problems in, for example, energy and health, demand viable universal solutions.

Studies in my research group are focused around the discovery and use of catalytic reactions to deliver novel molecular structures. In this talk a summary of recent discoveries in organocatalysis,1 transition metal catalysis,2 and biocatalysis3will be provided focusing on the ways that new synthesis can address unmet challenges in society.


David W. Lupton graduated with a Bachelor of Science (Honors, 1st class) in 2001 (University of Adelaide) before being awarded a Doctorate of Philosophy for studies under the supervision of Professor Martin G. Banwell (Australian National University) in 2005. Dr. Lupton then undertook a postdoctoral fellowship with Professor Barry M. Trost (Stanford University, USA) as a Sir Keith Murdoch fellow of the American Australian Association. In 2007 he returned to Australia to take up an academic appointment at Monash University in Melbourne , receiving an Australian Research Council Future Fellowship in 2011. In addition, in 2010 he received the Athel Beckwith Lectureship of the Royal Australian Chemical Institute (RACI), and in 2012 a Thieme journal award of the Organic Editorial Board. In 2013 he received the Rennie Medal of the RACI. In 2015 he received the Alexander von Humboldt Ludwig-Leichardt Awardee for studies with Professor Herbert Mayr. He has served as the Associate Head of Research within the School of Chemistry and was promoted to Professor in 2018.

New Strategies for Synthesizing Bioactive Alkaloids

DAWEI MAShanghai Institute of Organic ChemistryShanghai, China

In this lecture we report our recent efforts toward the total synthesis of alkaloid by developing new synthetic strategies, which include total syntheses zaitine and navirine C by using a chelation-triggered conjugate addition to a,b-unsaturated nitrile and oxidative-dearomatization/Diels-Alder cycloaddition as the key steps; a short and convergent route for assembling gelsedine alkaloids, and total synthesis of lipidilectine B by installing its spiro indoline and lactone units through a manganese(III)-mediated oxidative cyclization of a 1,2,3-trisubstituted indole.


Dr. Dawei Ma received his PhD in 1989 from Shanghai Institute of Organic Chemistry (SIOC), and did his postdoctoral studies at the University of Pittsburgh and Mayo Clinic. He returned to SIOC in 1994, and was appointed as research professor in 1995. He is presently the deputy director of SIOC and an associate editor of Journal of Organic Chemistry. His research interests currently focus on the development of new synthetic methodologies, the total synthesis of complex natural products and their SAR and action mode studies, as well as the discovery of small modulators for target proteins and special biological processes.

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Development and Application of Tyrosine Click Reaction

SHINICHI SATOTokyo Institute of TechnologyKanagawa, Japan

The chemical modification of proteins with synthetic probes is an important technique in chemical biology, protein-based therapy, and material science. In addition to conventional modification methods that target nucleophilic amino acid residues such as lysine and cysteine residues, alternative methods that can modify other amino acid residues, such as tyrosine or tryptophan residues, have attracted immense attention recently. In the attempt to modify native proteins, we developed tyrosine-specific bioconjugation reaction.

Based on the report by Barbas et al. (JACS 2010) in which diazodicarboxyamide compound modifies tyrosine via ene-type reaction, we thought that a reactive diazodicarboxyamide would enable us to modify the tyrosine residue efficiently. In order to generate highly reactive diazodicarboxyamide in situ, we synthesized several hydrazide derivatives (CO-NH-NH-CO), the precursors of diazodicarboxyamide (CO-N=N-CO), and evaluated as the tyrosine modifier using various catalysts, including peroxidase, in the presence of a tyrosine-containing peptide. The optimized reaction conditions by the peptide experiments were applied to the protein chemical modification. In order to clarify the modified residues on the protein, enzymatic digestion of the modified protein with trypsin and LC-MS and MS/MS analyses were carried out.

We found that the N-methylated luminol derivative was activated by horseradish peroxidase (HRP), efficiently inducing covalent bond formation with tyrosine residue.

This labeling reaction selectively proceeded only at a tyrosine residue among all natural amino acid residues. Furthermore, the surface-exposed tyrosine residues underwent modification with N-methylated luminol derivative more efficiently than internal tyrosine residues.

We found that the N-methylated luminol derivative was efficiently activated by HRP to induce covalent bond formation with a tyrosine residue. This highly efficient tyrosine-specific modification method with high provides an attractive strategy not only for the modification of peptides but also for protein modification and immobilization.


Shinichi Sato received his B. Sc. Degree in 2006 from Meiji Pharmaceutical University, and his Ph. D. degree in 2011 form University of Tokyo (Professor Yuichi Hashimoto). He spent one year in Professor Carlos F. Barbas’s group at The Scripps Research Institute as a JSPS fellow. He joined the Department of Chemistry, Faculty of Science, Gakushuin University as an assistant professor in 2012. He is currently an assistant professor in Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology. He was awarded in Ajinomoto Award in Synthetic Organic Chemistry and The Pharmaceutical Society of Japan Kanto Branch Young Scientist Award.

Synthesis and Application of a Mechanism-Based Inactivator of Endo-(Xylo)Glucanase

NAMRATA JAINUniversity of British Columbia Vancouver, Canada

Glycoside Hydrolases (GHs) are a major class of carbohydrate-active enzymes (CAZymes) capable of catalysing glycosidic bond cleavage. The discovery and characterization of GHs targeting complex carbohydrates is of significant interest in the field of biomass utilization. Xyloglucan is a complex polysaccharide rich in the cell walls of all terrestrial plants, making it a valuable source of fermentable carbohydrates. As such, the discovery of xyloglucan-active enzymes is an active area of research. Small molecule glycomimetic mechanism-based covalent inhibitors are valuable tools to probe the active site of GHs, yielding valuable information about specificity and mechanism. The potential mechanism-based inhibitor XXXG(2F)-β-DNP was synthesized from the xyloglucan-derived heptasaccharide XXXG (Xyl3Glc4), which was produced from tamarind kernel powder enzymatically. It was then tested as an active-site label against five endo-(xylo)glucanases of differing origins. Detailed inhibition kinetic parameters for a representative, highly specific GH5 endo-(xylo)glucanase from the soil saprophyte Cellvibrio Japonicus (CjGH5D) were determined. Additionally, X-ray crystallography was used to examine the three-dimensional structure of the XXXG(2F)-CjGH5D covalent glycosyl-enzyme intermediate.Results : We were able to produce a stereochemically pure XXXG(2F)-β-DNP via a chemo-enzymatic synthesis. Through intact mass spectrometry, kinetics, and crystallography, we demonstrated that this compound is indeed an inhibitor of


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“retaining” endo-(xylo)glucanases, and specifically labels the catalytic nucleophile. Using protein crystallography, we subsequently directly mapped enzyme-substrate interactions in CjGH5D of a covalent inhibitor complex vis-à-vis a previously determined XXXG-N-bromoacetyl active-site-directed affinity ligand complex. The synthesis of the heptasaccharide XXXG(2F)-β-DNP has enabled the production of a structurally complex 2-deoxy-2-fluorosugar mechanism-based inactivator. Possessing specificity advantages over analogous xyloglucan oligosaccharide affinity-based inhibitors3, we anticipate that XXXG(2F)-β-DNP may find continued use in structure-function analyses of endo-(xylo)glucanases from diverse GH families.

Attia, M. A. & Brumer, H. Curr. Opin. Struct. Biol. 40, 43–53 (2016).

Attia, M. A. et al.. Biotechnol. Biofuels 11, 45–61 (2018).

Fenger, T. H. & Brumer, H. ChemBioChem 16, 575–583 (2015).


Namrata Jain received her Bachelor of Technology (B. Tech.) degree in Chemical Science and Technology from the Indian Institute of Technology Guwahati in 2012. Thereafter, she worked with Prof. Elizabeth Gillies at Western University in Canada and completed her M.Sc. in chemistry in 2014 on the synthesis of carbohydrate functionalized dendrons for use as multivalent scaffold and in self-assembled structure.

Subsequently, she joined Prof. Harry Brumer’s group at the Michael Smith Laboratories in the University of British Columbia to work on the synthesis of oligosaccharide-based covalent inhibitors of carbohydrate active enzymes (CAZymes) capable of yielding valuable information about the function, mechanism and specificity of individual glycoside hydrolases (GHs) by probing their active site and thus facilitating the understanding of specific pathways utilized by GHs in plant biomass degradation.

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Chemical Proteomics for Drug Target Engagement and IdentificationElucidating PARP Inhibitor Selectivity Using a PARP Family Affinity Matrix

ANDREW ZHANGAstraZenecaBoston, United States

The poly(ADP-ribose) polymerase (PARP) family consists of enzymes implicated in DNA damage response (DDR), and PARP inhibitors have seen widespread clinical application for cancers presenting deficiencies in homologous recombination. Identification of a comprehensive profile of targets inhibited by PARP inhibitors, particularly understanding their pan-PARP selectivity, is important generating hypotheses around differences in efficacy and toxicity. Immobilized chemical probes, including family affinity matrices, are very useful for probing target engagement and selectivity in a biologically relevant setting.

We generated an affinity matrix consisting a single promiscuous phthalazinone analogue capable of enriching up to 15 of the 17 known PARP enzymes, including those implicated in DDR (PARPs 1-3) and gut toxicity (Tankyrase).

Through reverse competition of PARPs binding in MDA-MB-436 BRCA-mutant lysate against the affinity matrix followed by a mass spectrometry-based readout, we profiled 5 clinical inhibitors (niraparib, olaparib, rucaparib, talazoparib, veliparib), showing their distinct PARP selectivity profiles in a disease relevant context. In-depth statistical analysis of dose response profiles performed with our in-house developed tool named DOSCHEDA (Downstream Chemoproteomics Data Analysis) identified putative binding partners and their interactions with PARP1.

We have developed a chemical proteomics assay to profile the selectivity of PARP inhibitors in biologically relevant settings across the PARP family and applied this towards understanding the pan-PARP selectivity of clinically relevant PARP inhibitors, generating hypotheses around their observed phenotypes in vitro and in vivo.


Andrew Zhang is an Associate Principal Scientist in the Chemical Biology Group at AstraZeneca. He joined AstraZeneca in 2013 with research interests in target deconvolution, particularly using chemical proteomics and orthogonal methods for identifying targets, profiling selectivity, and confirming engagement. Previously, he has conducted research at the interface between small molecules and antibodies, on small molecule immunomodulators as well as antibody-drug conjugates. He obtained a Bachelors of Science degree in Chemistry and a Bachelors of Arts degree in Molecular and Cell Biology from the University of California, Berkeley, and completed his PhD training with Professor David Spiegel at Yale University. Prior to joining AstraZeneca, he spent one year in the Drug Discovery Program at the Ontario Institute for Cancer Research (Toronto, Canada) as a postdoctoral fellow.

Applying Chemical Biology in the T790M-EGFR Program

SHERRY L NIESSENPfizerLa Jolla, United States

To enable a more complete understanding into the mechanism of action of covalent EGFR inhibitors we specifically explore the proteome-wide reactivity of a series of third-generation T790M-EGFR inhibitors in human cancer cells and animal models through the development and application of chemical probes and quantitative mass spectrometry-based proteomic methods. We identify that each T790M-EGFR inhibitor has a distinct off-target labeling profile in cancer cells which is centered on the engagement of proteins with functional and ligandable cysteines. These studies highlight the importance of performing global analyses of drug action in living systems to identify targets and off-targets that may impact efficacy and safety.


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Sherry Niessen obtained her PhD at Scripps Research Institute (TSRI) in the lab of Dr. Benjamin Cravatt, and remained as a Scipps staff scientist at The Center for Physiological Proteomics prior to joining Pfizer in 2012 where she is currently a Principal scientist, Worldwide Medicinal Chemistry. Sherry is a chemical biologist with 12 years of interdisciplinary research experience bridging chemical biology, proteomics (applying; LTQ, Orbitrap, Velos, QE), metabolomics (applying; QQQ, qTOF), cell and molecular biology.

Sherry’s research is currently focused on the identification and characterization of therapeutic protein targets of small molecules.

Education: 2005-2008 The Scripps Research Institute (TSRI), La Jolla, USA Ph.D. in Cell Biology and Chemical Physiology Laboratory of Dr. Benjamin Cravatt 2000-2004 McGill University, Montreal, Canada M.Sc. in Experimental Medicine Laboratory of Dr. Guy Sauvageau 1995-2000 Simon Fraser University, Burnaby, Canada B.S. in Biochemistry Positions: Pfizer Principal scientist (R5), Worldwide Medicinal Chemistry, La Jolla (2012-current). The Scripps Research Institute 1) Staff Scientist, The Center for Physiological Proteomics (CPP) (2008-2012).

Targeted Protein Degradation: Tools for Target Evaluation and Therapeutic Applications

ANDREW J. PHILLIPSC4 TherapeuticsWatertown, United States

This talk will provide a brief introduction to targeted protein degradation and will highlight two specific applications of this rapidly emerging technology: the degradation of BET bromodomain proteins for therapeutic impact in leukemias and the introduction of ATAG – an ‘open-source’ toolkit designed to enable the chemical biology community to evaluate the degradation of targets both in vitro and in vivo.


Andy Phillips is President and Chief Executive Officer of C4 Therapeutics, a biotech company that is developing a new class

of small molecules that direct the machinery of the ubiquitin-proteasome system to selectively degrade disease-relevant proteins for therapeutic benefit.

Before joining C4 Therapeutics, Andy was Senior Director, Center for Development of Therapeutics at the Broad Institute of MIT and Harvard, where he led overall therapeutic efforts and provided strategic leadership for a number of major partnerships. Previously, he was a Full Professor of Chemistry at Yale University, where he received the ACS Cope Scholar Award for his research accomplishments, which included the development of small molecules aimed at modulating ‘undruggable’ targets. Prior to this, he was a Full Professor of Chemistry and Biochemistry at the University of Colorado at Boulder, where his efforts in complex molecule synthesis and targeting protein-protein interactions garnered a number of awards, including an Alfred P. Sloan Research Fellowship, an Eli Lilly Grantee Award, and a National Science Foundation CAREER Award. Andy received a B.Sc. (Hons) in biochemistry and a Ph.D. in biochemistry and chemistry from the University of Canterbury in New Zealand and completed a postdoctoral fellowship in organic chemistry at the University of Pittsburgh.

Bioorthogonal Chemical Probes to Interrogate Protein Acetylation

Y. GEORGE ZHENGUniversity of GeorgiaAthens, United States

Acetylation of lysine residues is one of the most important posttranslational modifications that diversify protein functions by changing protein stability, location, and protein-protein interaction. This process is mediated by Lysine acetyltransferases (KATs). Although housands of acetylated lysine residues have identified, there is a missing link connecting the compositions of the cellular acetylome networks to the enzymatic activities of different KAT members. The outstanding challenge is how to dissect the subacetylomes of individual KATs and address their functions on the proteomic scale.

We have explored a bioorthogonal profiling of protein acetylation strategy to label substrates of KAT enzymes. In this strategy, engineered KAT enzymes were created in conjugation with matching synthetic acetyl-CoA molecules to form orthogonal labeling pairs for KAT substrate labeling, identification, and profiling.

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A suite of Ac-CoA analogs containing either alkynyl or azido functional group (e.g. 3AZ-CoA, 4AZ-CoA, 4PY-CoA, 5HY-CoA, 6HY-CoA) were synthesized as potential cofactor surrogate for selective labeling of KAT substrates. Meanwhile, the active site of the KATs was engineered in order to expand the cofactor binding capability of the enzymes to accommodate the bulkier synthetic cofactors. Biochemical screening was conducted to identify matching KAT-cofactor pairs to efficiently label protein and peptide substrates of KATs with alkyne or azide warhead. We found out that several GCN5 mutant forms exhibited appreciable activities to the synthetic cofactors. MOF-I317A was active toward all the Ac-CoA analogs. No mutation is needed as the wild-type p300 exhibited robust activity to 4PY-CoA and 3AZ-CoA. The acylated substrates can be selectively linked through the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction with fluorescent reporter or biotin affinity tag for optical imaging or protein enrichment on streptavidin-coated resin. We have successfully used this bioorthogonal technology to profile substrates of p300 and GCN5 in the context of complex cellular proteomes.

We have created a bioorthogonal, chemoproteomic strategy to investigate KAT biology which provides a powerful enabling technology for activity-based lysine acylation profiling on proteomic scale. Our KAT activity profiling demonstrates extensive engagement of KATs in cellular pathways and provides new molecular insights into understanding their functions in biological processes.


Y. George Zheng received his B.S. in chemistry at Peking University, Ph.D. at University of Miami, and postdoctoral training at Johns Hopkins University School of Medicine. From 2006 to 2013, He was an Assistant Professor and Associate Professor in the Department of Chemistry at Georgia State University. Since 2013, he has been an Associate Professor and Professor in the Department of Pharmaceutical & Biomedical Sciences at University of Georgia. His research interest is on developing chemical probes and drug leads to target epigenetic enzymes.

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Biosensors and ImagingA Suite of New Fluorescent Biosensors for Dynamic Visualization of Cell Signaling in Living Cells

JIN ZHANGUniversity of California, San DiegoSan Diego, United States

I will discuss development and application of a suite of new fluorescent biosensors for visualizing signaling activties in living cells.


Jin Zhang received her PhD in Chemistry from the U. Chicago. After completing her postdoctoral work, she joined the faculty of Johns Hopkins University School of Medicine in 2003. She was promoted to Professor of Pharmacology, Neuroscience and Oncology in 2013. In 2015 she moved to University of California, San Diego as a Professor of Pharmacology, Biochemistry and Bioengineering. Research in her lab focuses on developing enabling technologies to probe the active molecules in their native environment and characterizing how these active molecules change in diseases including cancer. Professor Zhang is a recipient of the NIH Director’s Pioneer Award (2009), the John J. Abel Award in Pharmacology from ASPET (2012), the Pfizer Award in Enzyme Chemistry from ACS (2012), and NCI Outstanding Investigator Award (2015). She was elected as a Fellow of the AAAS in 2014. She serves on the editorial advisory board of Cell Chemical Biology and is the Secretary/Treasurer of ASPET.

New Colours and Applications of Genetically Encoded Biosensors to Probe Cell Signaling

ROBERT CAMPBELLUniversity of Alberta and The University of TokyoEdmonton, Canada

The advent of optogenetic tools, broadly defined here as both actuators for cell control and indicators for cell visualization, has revolutionized our ability to spy on the otherwise invisible world of neuronal activities. The most versatile class of optogenetic indicators are the Ca2+ indicators that change their fluorescence intensity or color in response to intracellular signaling events. These indicators are frequently used in combination with optogenetic actuators to enable simultaneous control and visualization of cellular signalling with precise spatial and temporal resolution. However, a persistent challenge in this area is achieving sufficient spectral separation between the wavelengths of light required to excite the actuator and the indicator. In this seminar I will describe our most recent efforts to use protein engineering to make highly red-shifted genetically encoded Ca2+ indicators that are suitable for use in combination with blue-light activatable optogenetic actuators. In addition, I will discuss recent progress to develop new application of our blue-light photocleavable optogenetic actuator, PhoCl.


Dr. Robert E. Campbell is a Professor in the Department of Chemistry, University of Alberta (2003 - present). As of July 2018 he has a 50% appointment as Professor in the Department of Chemistry at the The University of Tokyo, and 50% appointment at the University of Alberta. He earned his Ph.D. in Chemistry with Martin Tanner at the University of British Columbia in 2000 and undertook postdoctoral research at the University of California San Diego in the lab of the late Roger Y. Tsien (2008 Nobel Prize). He is a leading developer of optogenetic tools, including red fluorescent Ca2+ indicators used in labs around the world. He has distributed >5000 samples of optogenetic tools through the Addgene plasmid repository and many others are distributed as viral vectors. Recent recognitions include a

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Stanford Neurosciences Institute Visiting Scholar Award (2017), the Teva Canada Limited Biological and Medicinal Chemistry Award (2016), the Rutherford Memorial Medal from the Royal Society of Canada (2015), and the Boehringer Ingelheim Research Excellence Award (2014). He has multiple patents awarded or pending.

Shortwave Infrared Fluorophores for Illuminating Biological Processes In Vivo

ELLEN M. SLETTENUCLALos Angeles, United States

Chemical biologists have created a plethora of fluorescent probes that allow biological processes to be studied in real time. These methods have been exceedingly successful in cells and transparent organisms, but are less effective in higher mammals due to the limited penetration of light through tissue.

Recently, the shortwave infrared (SWIR) region of the electromagnetic spectrum has emerged as the premier region for optical imaging in mammals; however, there are limited fluorophores for use at SWIR wavelengths. Our group develops new fluorophores for the SWIR region of the electromagnetic spectrum. We focus on polymethine dyes and modify the heterocycles to tune the absorption, emission, absorption coefficient, quantum yield, and solubility of the fluorophores.

We have found that polymethine dyes with dimethylamino flavylium heterocycles display significantly red-shifted absorption and emission compared to traditional indolene-containing polymethine dyes (cyanine dyes). The dimethylamino flavylium heptamethine dye, deemed Flav7, emits at 1045 nm with quantum yield of ~ 0.6%, which is larger than commercially available SWIR polymethine fluorophores. We have prepared micelle formulations of Flav7 and obtained high-resolution optical images in mice. Additional work has surrounded modification of the dimethylamino flavylium heterocycles leading to enhanced photophysical properties and improved nanomaterial formulations.

The SWIR region of the electromagnetic spectrum allows for optical imaging in animals with superior resolution and/or depth penetration as compared to the visible and near infrared regions. The development of polymethine fluorophores for the SWIR region will facilitate the extension of optical chemical biology tools to mammals.


Dr. Ellen Sletten is an Assistant Professor in the Department of Chemistry and Biochemistry at UCLA. She obtained her B.S. in Chemistry from Stonehill College in 2006 and PhD in Chemistry from UC Berkeley in 2011. Her thesis work was performed in Dr. Carolyn Bertozzi’s laboratory on the development of bioorthogonal chemistries. Upon graduation, Dr. Sletten moved to Massachusetts Institute of Technology as an NIH postdoctoral fellow in Dr. Timothy Swager’s group exploring dynamic fluorescence-based sensors. In 2015, Dr. Sletten began her independent career at UCLA, where she has established an interdisciplinary research program that leverages the tools of physical organic chemistry to create new optical chemical tools and theranostic technologies.

Selectivity Differences Between Cellular and Biochemical Analysis

PONCHO MEISENHEIMERPromega BiosciencesSan Luis Obispo, United States

Quantitative assessment of kinase target occupancy in live cells, under a thermodynamic equilibrium with the drug molecule, better reflects drug affinity under physiologically relevant local ATP concentrations. Here we report the application of an energy transfer technique (NanoBRET) that enables the first quantitative approach to profile target occupancy, compound affinity, and residence time for a broad spectrum of intracellular kinase enzymes. Using this technique, target occupancy data correlates quantitatively with traditional intracellular activity/pathway analysis readouts. This method allows for broad-spectrum profiling of inhibitor selectivity against nearly 300 kinases, in a simple work-flow. We performed a systematic comparison of kinase inhibitor selectivity in live cells versus biochemical analyses. Compared to published biochemical profiling results, we observed an improved intracellular selectivity profile for certain clinically-relevant multi-kinase inhibitors. Moreover, this technique allowed for a mechanistic interrogation of micro-environmental ATP levels on engagement potency. When performed in real time, this technique enables a readout of compound residence time further supporting the quantitative nature of this occupancy measurement. When target engagement analysis is performed under equilibrium and non-equilibrium conditions, surprising kinetic selectivity profiles are observed for certain clinically-relevant kinase inhibitors.


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As Director of Chemistry Research for Promega, Poncho has long focused on live cell detection of the interactions between endogenous and exogenous molecules. This group develops intracellular pro-luminescent probes for enzyme and biomolecule detection, fluorescent tracers for energy transfer target engagement assays, novel fluorescent dye development, novel bioluminescent substrates, and live cell selective protein labels.

Additionally, Poncho has lead chemistry research programs in drug development to enable drug assisted psychotherapies, fluorescent amidite development to enable forensic

DNA analysis, polymer development to enable capillary electrophoresis, and magnetic microparticle development to enable automated genomics.

He serves on the Scientific Advisory Board for the Usona Institute and for the Chemical Probes Portal, and has currently co-authored over 30 journal articles/reviews and is an inventor for 29 issued patents and 81 pending patent applications. Poncho received his Ph.D. in Organic Synthesis at University of Colorado–Boulder and served on the faculty at California Polytechnic State University–SLO prior to joining Promega Corporation in 2001.

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ICBS 2018 Rising Stars Sponsored by ACS Chemical Biology

Rising StarsTo advance the career development of young investigators in chemical biology, ICBS has established a special session at the Annual Meeting to showcase up-and-coming chemical biology scientists. The selected recipients will give a podium presentation during the special “Rising Stars” session, and each will be further recognized for their achievements with a certificate and a monetary award.

Proximity-Directed O-GlcNAc Transferase for Protein-specific O-GlcNAcylation

CHRISTINA WOOHarvard UniversityCambridge, United States

Over 15% of the cellular proteome is modified by O-linked N-acetyl glucosamine (O-GlcNAc), a post-translational modification that consists of a single glucosamine monosaccharide attached to serine or threonine residues of nuclear, cytosolic and mitochondrial proteins. Due to the ubiquitous nature of the modification, O-GlcNAc has been implicated in numerous biological processes, including immune response, cancer progression, neurodegeneration, and diabetes. Despite a number of studies that point to the critical biological impact of O-GlcNAc on specific proteins, delineation of the function of O-GlcNAc modification on particular glycoproteins are hindered by the inability to control O-GlcNAc stoichiometry on specific proteins of interest in cells. A general method to control glycosylation on specific target proteins would enable the systematic evaluation of O-GlcNAc function in cells.

To advance insight into the role of O-GlcNAc on specific proteins, we developed fusions of O-GlcNAc transferase (OGT) to nanobodies as proximity-directing agents to a target protein and

increase O-GlcNAc levels in live cells. Fusion of the nanobody to full-length OGT(13), possessing 13 tetratricopeptide repeats (TPRs), or a truncated OGT(4), possessing 4 TPRs, displayed analogous glycosyltransferase activity in cells. Proximity-induced glycosylation was demonstrated on ten nucleocytoplasmic proteins representing the broad array of substrates for OGT. Isotope targeted glycoproteomics (IsoTaG) was used to map specific glycosites yielded by proximity-induced glycosylation.

In all evaluated target proteins, co-transfection with nanobody-OGT(13) or nanobody-OGT(4) increased O-GlcNAc stoichiometry on the target protein. Evaluation of the effect of O-GlcNAc on some target proteins revealed altered subcellular localization. The changes in subcellular localization was attributed to increasing O-GlcNAc stoichiometry and scaffolding functions from OGT itself.

We report the ability to induce O-GlcNAc to specific proteins in live cells through introduction of an orthogonal, defined nanobody domain to OGT. The nanobody domain can replace part of the TPR domain, resulting in reduced innate substrate recognition through the TPR domain and generated more selective constructs that increase O-GlcNAc levels on a range of nucleocytoplasmic proteins. Manipulation of O-GlcNAc stoichiometry using proximity-directed OGT will catalyze additional discoveries of functions for O-GlcNAc and OGT itself.


Christina M. Woo obtained a BA in Chemistry from Wellesley College (2008) and obtained her PhD in 2013 from Yale University under the guidance of Professor Seth B. Herzon. In 2013, Christina joined the laboratory of Professor Carolyn R. Bertozzi at the University of California Berkeley as a Jane Coffins Child postdoctoral fellow and and Stanford University as a Burroughs Wellcome Fund CASI Fellow. Christina joined the Department of Chemistry and Chemical Biology at Harvard University as an Assistant Professor in 2016, where her group is studying chemoproteomic signaling using chemical biology and mass spectrometry methods to map and manipulate small molecule protein interactions.


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Chemoproteomics Profiling Reveals the Anti-Steatosis Mechanism of a Natural Flavonoid

CHU WANGCollege of Chemistry and Molecular Engineering Peking University, China

Hepatic steatosis, marked as excessive lipid accumulation in hepatocytes, constitutes the early stage of non-alcoholic fatty liver diseases (NAFLD), a world-wide epidemic that is strongly implicated with obesity and metabolic disorders. A natural flavonoid compound isolated from Chinese herbal medicine was shown with strong anti-steatosis effect, however, the mechanism of action remains elusive.

We employed a quantitative chemical proteomic strategy to deconvolute the protein targets of this compound. Photo-affinity probes were synthesized, SILAC-based chemical proteomics experiments were performed and multiple targets were identified.

Guided by functional pathway analysis, we discovered that the flavonoid binds to a key enzyme in the fatty acid oxidation pathway and allosterically activates the enzyme to accelerates the rate of fatty acid degradation in the liver. Oral administration of the compound significantly ameliorates the symptoms associated with diet-induced obesity and hepatic steatosis.

Our work revealed the mechanism of action of a natural flavonoid compound with unique anti-steatosis activity and suggested that flavonoids may serve as a common scaffold to develop novel drugs for pharmacological treatment of NAFLD.


Dr. Chu Wang obtained his B.S. degree in Biology from University of Science and Technology of China (USTC) in 2001 and his Ph.D. degree with Professor David Baker in 2007 from University of Washington. He did his postdoctoral training with Professor Benjamin F. Cravatt at The Scripps Research Institute from 2009 to 2013 and was supported by NIH / NIEHS Pathways to Independence (K99/R00) postdoctoral award. He started as an

assistant professor at Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University in December, 2013 and is also affiliated with Synthetic and Functional Biomolecules Center (SFBC) and Peking-Tsinghua Center for Life Sciences (CLS) as a Principal Investigator. His current research programs focus on the development and application of multi-disciplinary tools in chemical proteomics, biochemistry and computational biology to streamline efforts in global profiling and discovery of functional sites, post-translational modifications and biomolecular interactions in proteomes.

Decoding Protein Adp-Ribosylation Networks in Cells Using Chemical Genetic Approaches

MICHAEL COHENOregon Health and Science University, USA

ADP-ribosylation (ADPr) is a reversibleposttranslational modification that is essential for cellular function, yet little information exists regarding relevant protein substrates and target specificity. ADPr is catalyzed by a family of 17 enzymes in humans known as poly-ADP-ribose-polymerases (PARP1-16 in humans; also known as ARTDs), which transfer the ADP-ribose moiety from nicotinamide adenine dinucleotide (NAD+) to amino acids on target proteins. The PARP family is sub-classified based on the ability of the individual PARP enzymes to catalyze the transfer of a single ADP-ribose unit (mono-PARPs: PARP3, 6-8, 10-12, 14-16) or multiple ADP-ribose units (poly-PARPs: PARP1-2, 4, 5a, 5b) onto target proteins. Progress in understanding the specific role of a given PARP in cells has been severely limited by the inability to identify the direct targets for individual PARPs in a cellular context.

To address this challenge, my laboratory has designed novel orthogonal NAD+analog-engineered PARP pairs for the identification of direct protein targets of individual PARPs. The orthogonal NAD+ analog contains a benzyl group at the C-5 position of the nicotinamide ring, which interacts with a hydrophobic pocket uniquely found in the engineered PARPs, and an alkyne tag at the N-6 position on the adenosine ring for copper-catalyzed

ICBS 2018

49


conjugation to a biotin−azide probe. We have successfully applied our chemical genetic approach toward the identification of the direct targets of the poly-PARP subfamily, and have recently extended this strategy to the mono-PARP subfamily.

I will discuss our unpublished work on identifying the direct targets of the mono-PARP, PARP14. PARP14 is involved in normal immune function through the IL-4 signaling pathway and is a pro-survival factor in multiple myeloma and hepatocellular carcinoma. Combining our chemical genetics approach with a BioID approach for proximity-dependent labeling of PARP14 interactors, we identified 114 PARP14-specific protein substrates, several of which are RNA regulatory proteins. One of these targets is PARP13, a protein known to play a role in regulating RNA stability. PARP14 MARylates PARP13 on several acidic amino acids.

This study not only reveals crosstalk among PARP family members but also highlights the advantage of using disparate approaches for identifying the direct targets of individual PARP family members.


Michael Cohen received his B.S. in Chemistry from University of California, Irvine. His interest in the chemistry and biology interface led him to pursue a Ph.D. in Chemistry and Chemical Biology at the University of California, San Francisco under the supervision of Jack Taunton. In his graduate studies, he developed structural bioinformatics-based approaches for generating selective protein kinase inhibitors. He then pursued postdoctoral studies with Samie Jaffrey at Cornell Medical College where he investigated compartmentalized NAD+ biosynthesis. In 2011, he began his independent career at Oregon Health and Science University where his lab is focused on using chemistry-based approaches to investigate NAD+ signaling. His lab is particularly interested in enzymes known as PARPs, which are the major consumers of NAD+ in the cell and mediate post-translational modification known as ADP-ribosylation. Over the last several years, his lab has developed novel chemical tools which have revealed new roles for PARPs and ADP-ribosylation in cells.

Past Rising Stars2017

Toru KomatsuUniversity of Tokyo

Qi ZhangFudan University

Haitao ZhangZhejiang University

2016

Yimon AyeCornell University

Ratmir DedraUniversity of Alberta

William PomerantzUniversity of Minnesota

2015

Alessio Ciulli University of Dundee, UK

Edward LemkeEMBL, Germany

Evan Miller University of California Berkley

2014

Evripidis Gavathiotis Albert Einstein College of Medicine

Kenjiro Hanaoka University of Tokyo

Jiaoyang Jiang University of Wisconsin-Madison

2013

Bradley L. Pentelute, Massachusetts Institute of Technology

Christian Ottmann, Eindhoven University of Technology, Netherlands

Xiaoguang Lei,

National Institute of Biological Sciences, China


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Poster PresentersPresenter Poster Title

Board Number

Category

Hong Yee TanDIRECT FLUORESCENT LABELING OF O-GLCNAC MODIFIED PROTEINS IN LIVE CELLS USING METABOLIC INTERMEDIATES AS PRECURSORS

P-02 Glycobiology

Seyed NasseriA NOVEL MECHANISM BASED APPROACH FOR SCREENING METAGENOMIC LIBRARIES FOR UNUSAUL GLYCOSIDASES

P-03 Glycobiology

Kenjiro HanaokaDEVELOPMENT OF A SERIES OF FLUORESCENCE PROBES TO MEASURE PH VALUES IN LIVING SAMPLES

P-04 Imaging Tools

Takayuki IkenoDEVELOPMENT OF AN ACTIVATABLE PHOTOACOUSTIC PROBE FOR HYPOCHLOROUS ACID

P-05 Imaging Tools

Heather ArnaizINNOVATIVE APPROACHES FOR SECURE, MODERN COLLABORATIVE DRUG DISCOVERY

P-07 Medicinal Chemistry

James Meinig TARGETED PRODRUGS FOR CNS-SELECTIVE DRUG DISTRIBUTION P-08 Medicinal Chemistry

Jeffrey Y.K. WongALBUMIN-BINDING PENTAFLUOROPHENYL-SULFIDE PEPTIDE MACROCYCLE WITH EXTENDED CIRCULATION HALF-LIFE IN VIVO


Dennis LiuEXPLOITING CHEMICAL SYNTHETIC-LETHAL INTERACTIONS TO TARGET ANTIMICROBIAL-RESISTANT PATHOGENS

P-10 Natural Products Chemistry

Fred HaecklA SELECTIVE GENOME-GUIDED METHOD FOR ENVIRONMENTAL BURKHOLDERIA ISOLATION


Joseph Egan USING NMR TO UNLOCK CHEMICAL DIVERSITY FROM NATURAL PRODUCT EXTRACTS P-12 Natural Products Chemistry

Nicole LeGrowNATURAL PRODUCTS LIBRARY DIVERSIFICATION THROUGH CHEMICAL TRANSFORMATION


Jasmine Li-BrubacherDEVELOPMENT OF A CHEMICAL BIOLOGY SCREEN FOR INHIBITORS OF STOP-GO TRANSLATION

P-14 Other

Julian WilkeIDENTIFICATION OF CYTOTOXIC, GLUTATHIONE-REACTIVE MOIETIES INDUCING ACCUMULATION OF REACTIVE OXYGEN SPECIES VIA GLUTATHIONE DEPLETION

P-15 Other

Karson Kump TARGETING MCL-1 TO OVERCOME RESISTANCE IN SOLID TUMORS P-16 Other

Thomas Garner ALLOSTERIC MODULATION AND THERAPEUTIC INHIBITION OF PRO-APOPTOTIC BAX. P-17 Other

Chloe GerakIN PURSUIT OF SMALL MOLECULE INHIBITORS OF ETV6 PNT DOMAIN POLYMERIZATION

P-19 Protein-Protein Interactions

Michael WinzkerPHOTOACTIVATABLE FARNESYL-ANALOGUES AS PROBES TO IDENTIFY PROTEIN-PROTEIN INTERACTIONS


Alena Istrate CYCLOPROPENONE REAGENTS FOR SITE-SELECTIVE CYSTEINE BIOCONJUGATION P-21 Synthetic Biology

Kenzo Yamatsugu SYNTHETIC HISTONE ACYLATION WITH CHEMICAL CATALYSTS P-22 Synthetic Biology

Ali NejatieIN SEARCH FOR AN AFKDNASE INHIBITOR: A POTENTIAL THERAPEUTIC FOR TREATING INVASIVE ASPERGILLOSIS

P-23 Synthetic Chemistry

Barbara Sohr CHEMICAL PROBES FOR INTRACELLULAR HYPOXIA TARGETING P-24 Synthetic Chemistry

Charlotte ZammitPROGRAMMABLE CHEMICAL ASSEMBLY OF NON-NATURAL AMINO ACIDS USING DNA-TEMPLATED ORGANIC SYNTHESIS

P-25 Synthetic Chemistry

Nicole Houszka INTRACELLULAR BIOORTHOGONAL CLEAVAGE P-26 Synthetic Chemistry

Saiko ShibataDEVELOPMENT OF SMALL MOLECULE COMPOUNDS FOR TREATMENT OF PATIENTS WITH CYSTIC FIBROSIS CARRYING THE SPLICING MUTATION

P-27Target Engagement/Mechansims

Wansang ChoDIFFERENTIAL REGULATION OF PRO-INFLAMMATORY CYTOKINE SECRETION VIA SMALL MOLECULE TARGETING RECYCLING ENDOSOMAL PROTEIN RAB11


Syusuke EgoshiA NOVEL SCENARIO OF BACTERIAL INFECTION IN PLANT: CORONATINE INDUCES STOMATAL OPENING THROUGH TWO DIFFERENT TARGET PROTEINS IN GUARD CELLS


Elena ReckzehCUTTING THE GLUCOSE SUPPLY OF CANCER CELLS BY MEANS OF SMALL MOLECULES


Mathieu SoetensNEW PALLADIUM CATALYSTS FOR IN CELLULO PROBE UNCAGING: FROM THE BENCH TO CELLS

P-33 Imaging Tools

ICBS 2018

53


Presenter Poster Title Board

NumberCategory

Michihiko TsushimaSELECTIVE PURIFICATION AND LABELING OF LIGAND-BINDING PROTEINS ON RUTHENIUM PHOTOCATALYST FUNCTIONALIZED AFFINITY BEADS

P-35 Other

Anna Rutkowska-KluteA CLICK PROBE-BASED APPROACH FOR VISUALIZATION OF DRUG-TARGET INTERACTIONS AND TARGET ENGAGEMENT MEASUREMENT AT SINGLE CELL LEVEL


Koichi SasakiAFFINITY CONTROLLED INDUCTION OF ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY BY FC BINDING ANTIBODY RECRUITING MOLECULES


Guillaume Médard CHEMOPROTEOMICS-AIDED DRUG DISCOVERY P-38 Medicinal Chemistry

Polina Prokofeva PROTEOME-WIDE STRUCTURE-AFFINITY RELATIONSHIPS P-40 Medicinal Chemistry

Stephanie Heinzlmeir50 SHADES OF KINASE INHIBITION – APPLICATIONS OF THE TARGET LANDSCAPE OF CLINICAL KINASE DRUGS


Thota GaneshDEVELOPMENT OF EP2 ANTAGONISTS: FROM ASSAY DEVELOPMENT TO PRECLINICAL LEAD OPTIMIZATION.


Shireen JoziNITRIC OXIDE DONATING RUTHENIUM(II) COMPLEXES AS ANTICANCER AND ANTIBACTERIAL AGENTS


Kun QianCHEMICAL PROBE DISCOVERY TO INTERROGATE YAP-TEAD INTERACTION IN THE HIPPO SIGNALING PATHWAY


Phillip Danby GLYCOSIDE HYDROLASE CATALYZED HYDROLYSIS OF NON-GLYCOSIDIC LINKAGES P-48 Glycobiology

Victor FadipeANTIMYCOBACTERIAL AND CYTOTOXICITY STUDIES ON CINNAMIC ACID DERIVATIVE OF OLEANOLIC ACID AT C-28 POSITION


Amy Weeks MAPPING PROTEOLYSIS AT THE SURFACE OF LIVING CELLS P-55 Degradomics

Eline Sijbesma DISULFIDE TRAPPING FOR THE DISCOVERY OF SELECTIVE PPI MODULATORS P-56 Protein-Protein Interactions

Masayasu Toyomoto DRUG DISCOVERY BY RE-SEARCHING CANCER METABOLISM AND GPCR SIGNALING P-58 Other

Matthew Alteen CHEMICAL TOOLS FOR THE DISCOVERY OF O-GLCNAC TRANSFERASE INHIBITORS P-62 Glycobiology

Evan HaneyINFLUENCE OF NON-NATURAL AMINO ACIDS ON THE BIOLOGICAL ACTIVITY PROFILE OF SYNTHETIC HOST DEFENCE PEPTIDES


Sebastian Andrei PRINCIPLES BEHIND THE STABILIZATION OF PROTEIN-PROTEIN INTERACTIONS P-64 Medicinal Chemistry

Jason HedgesIN VITRO CHARACTERIZATION OF A CRYPTIC GENE CLUSTER ENCODING AN O2, PLP-DEPENDENT OXIDASE


Cameron Murray FINDING INHIBITORS OF PNKP TO TREAT PTEN DEFICIENT CANCERS P-67 Medicinal Chemistry

Lily TakeuchiLONG CIRCULATING SINGLE POLYMER NANOPARTICLES FORM A DYNAMIC PROTEIN CORONA IN VIVO

P-69 Other

Mirelle TakakiUNPRECEDENTED TAMBJAMINE ALKALOIDS DETECTED IN THE EXTRACT OF THE MANTLE OF THE NUDIBRANCH ROBOASTRA ERNSTI


Francois Jean

A MULTIPLEXED QUANTITATIVE TARGET ENGAGEMENT TECHNOLOGY TO DISCOVER AND VALIDATE THE MECHANISM OF BROAD-SPECTRUM ANTIPROTEOLYTIC DRUG CANDIDATES: N-TERMINAL ACETYL (NTAC)-MRM ASSAYS TO QUANTIFY HOST-MEDIATED ENDOPROTEOLYTIC CLEAVAGE OF ENVELOPE GLYCOPROTEIN PRECURSORS OF PATHOGENIC VIRUSES.


Akane Kawamura CYCLIC PEPTIDE TOOLS FOR EPIGENETIC PROTEINS P-73 Protein-Protein Interactions

Brent PageTARGETED NUDT5 INHIBITORS BLOCK HORMONE SIGNALING IN BREAST CANCER CELLS


Doug Auld INTRODUCTION TO THE FAST-LAB: NOVARTIS OPEN SPACE FOR COLLABORATIONS P-75 Other


54


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ICBS 2018

55

ICBS 20187th Annual ConferenceSeptember 24-27, 2018

Vancouver, Canada


7th annual conference icbs 2018€¦ · recording of sessions (oral or poster) by audio, video, or...

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