Frontiers in Chemical Biology and Drug Discovery

Friday, October 12, 2012

Charles B. Wang Center

S I X T H A N N U A L S Y M P O S I U M

Institute of Chemical Biology&Drug DiscoveryICB&DD

From the Director

The primary objective of the

Institute of Chemical Biology &

Drug Discovery (ICB&DD) is to

establish and sustain a world-class

“Center of Excellence” in chemical

biology and drug discovery at Stony

Brook University. The rapid and

impressive advancements in

chemical biology during the past

decade have clearly demonstrated that solutions for a vast

majority of medical problems rely on the understanding of

the molecular basis of diseases, therapeutic targets, drug

actions and drug resistance. ICB&DD promotes highly

productive interdisciplinary and collaborative research among

chemists, biologists, medicinal chemists, pharmacologists and

physicians to attack major biomedical problems to find

solutions, including the discovery of novel therapeutic drugs

and innovative diagnostic tools.

— Iwao Ojima, Director, Institute of Chemical Biology

& Drug Discovery

ICB&DD’s History and Mission

T he ICB&DD was established in 2004 with

institutional support from Stony Brook University

and the NYSTAR Faculty Development Award.

One of the institute’s strengths is that it was founded by

reorganizing existing exceptional talents on campus; thus at

its core is a well-proven entity with an excellent track record:

The primary members of ICB&DD currently hold more than

$23 million in National Institutes of Health (NIH) grants.

ICB&DD is open to a wide range of collaborative research

programs with pharmaceutical and biotechnology industrial

firms. ICB&DD members are from the departments of

Applied Mathematics and Statistics, Biochemistry and

Cellular Biology, Chemistry, Medicine, Molecular Genetics and

Microbiology, Oral Biology and Pathology, Pharmacological

Sciences, Physiology and Biophysics, and from the Cancer

Center, Center for Infectious Diseases, Center for Structural

Biology and Brookhaven National Laboratory’s Department

of Biology. In addition, ICB&DD has two laboratories located

in the Chemistry Building: Analytical Instrumentation

Laboratory and Discovery Chemistry Laboratory.

ICB&DD has three programs: Cancer Research,

Infectious Diseases Research, and Structural and

Computational Biology. ICB&DD, in collaboration with

the School of Medicine, has established the Translational

Experimental Therapeutics Laboratory to streamline the

preclinical evaluations leading to the Investigational New

Drug filing to the FDA. ICB&DD is working with the Stony

Brook University Cancer Center to develop a cancer

therapeutics program. ICB&DD also integrates existing

strengths at Stony Brook University in the basic medical

sciences as well as in medicinal chemistry, and brings in

complementary expertise from outside to explore drug

discovery and development. At present, ICB&DD focuses on

drug discovery in cancer therapeutics, infectious diseases and

therapeutics for diabetes. Through ICB&DD connections,

collaborative research teams have been created and research

proposals have been submitted to NIH and other funding

agencies. Currently, there are 26 ICB&DD-designated

projects (total funding: approximately $23.5 million).

Dr. Iwao Ojima received his BS, MS and PhD (1973) degrees fromthe University of Tokyo, Japan. He joined the Sagami Institute ofChemical Research and held the position of senior research fellow until1983. He joined Stony Brook University’s Department of Chemistry asan associate professor (1983), was promoted to professor (1984),leading professor (1991) and then to distinguished professor (1995).He served as the department chair from 1997 to 2003. Dr. Ojima hasbeen serving as the founding director for the ICB&DD since 2003. Hehas a wide range of research interests in synthetic organic andmedicinal chemistry as well as chemical biology, including discoveryand development of anticancer agents and antimicrobials, targeteddrug delivery, catalytic methodologies and asymmetric synthesis. Hisawards and honors include: Arthur C. Cope Scholar Award (1994), E.B. Hershberg Award for Important Discoveries of Medicinally ActiveSubstances (2001), Medicinal Chemistry Hall of Fame (2006) and ACS Award for Creative Work in Fluorine Chemistry (2013, named)from the American Chemical Society, The Chemical Society of JapanAward (1999), and Outstanding Inventor Award (2002) from the SUNYResearch Foundation. In addition, he is a fellow of the J.S. GuggenheimMemorial Foundation, American Association for the Advancement ofScience, New York Academy of Sciences and American Chemical Society.

Frontiers in Chemical Biology and Drug DiscoveryFriday, October 12, 2012

9:30 am to 9:45 am Moderator: Dr. Todd Miller (Chair of the Organizing Committee)Opening Remarks

Dr. Iwao Ojima, Distinguished Professor and Director, Institute of Chemical Biology & Drug Discovery, Stony Brook University

9:45 am to 10:30 am Moderator: Dr. Elizabeth BoonDr. Bonnie L. Bassler, Howard Hughes Medical Institute Investigator and Squibb Professor of MolecularBiology, Princeton University“Manipulating Quorum Sensing to Control Bacterial Pathogenicity”

10:30 am to 11:15 am Moderator: Dr. Dan RaleighDr. Jeffery W. Kelly, Chairman, Department of Molecular and Experimental Medicine, Department of Chemistry,The Scripps Research Institute“Biological and Chemical Approaches to Adapt Proteostasis to Ameliorate Protein Misfolding andAggregation Diseases”

11:15 am to 12 pm Moderator: Dr. James BliskaDr. Holger Sondermann, Associate Professor, Department of Molecular Medicine, Cornell University“The Ins and Outs of c-di-GMP Signaling in Bacterial Biofilm Formation”

12 pm to 1 pm Lunch

Chapel (invited faculty only); Zodiac Gallery (students)

1 pm to 1:45 pm Moderator: Dr. Stanley ZuckerDr. Basil Rigas, Professor of Medicine and Pharmacological Sciences; Vice President for Business Development,Dean for Clinical Affairs and Director of Cancer Prevention, School of Medicine, Stony Brook University“Modified NSAIDS and Cancer”

1:45 pm to 2:30 pm Moderator: Dr. Jessica SeeligerDr. Deborah Hung, Center for Computational and Integrative Biology and Department of Molecular Biology,Massachusetts General Hospital; Department of Microbiology and Immunobiology, Harvard Medical School;Broad Institute of MIT and Harvard University“Chemical Biological Approach to TB: Identifying New Drug Targets”

2:30 pm to 3:30 pm Coffee Break and Student Poster Session

Theater Lobby

3:30 pm to 4:15 pm Moderator: Dr. Peter TongeDr. Elizabeth Boon, Assistant Professor, Department of Chemistry, Stony Brook University“Nitric Oxide Signaling in Bacteria: Discovery of a New Mechanism for Regulating Bacterial Group Behavior”

4:15 pm to 5 pm Moderator: Dr. Todd MillerDr. David Lawrence, Professor, Division of Medicinal Chemistry and Natural Products, School of Pharmacyand Department of Chemistry, University of North Carolina at Chapel Hill“Organic Chemistry at the Edge of Biology: Taming Cell Behavior With Light Responsive Molecules”

5 pm Closing Remarks: Dr. Todd Miller

5:05 pm to 5:45 pm Reception and Poster Session (two poster awards)

Theater Lobby

5:45 pm to 6 pm Announcement of Poster Awards: Dr. Todd Miller

Theater Lobby

6 pm Dinner

Chapel

Dr. Jeffery W. Kelly is the LitaAnnenberg Hazen Professor of Chemistryin the Department of Chemistry andchairman of the Department of Molecularand Experimental Medicine at TheScripps Research Institute. He alsoserved as vice president of AcademicAffairs and dean of Graduate Studies atScripps for nearly a decade. Kelly is aleading scientist in the field of chemicalbiology. His research is focused on

uncovering protein folding principles, understanding the etiology ofprotein misfolding and/or aggregation diseases, and using thisinformation to develop novel therapeutic strategies.

Kelly’s work has appeared in more than 250 publications and hehas received many awards, among them The American ChemicalSociety Ralph F. Hirschmann Award in Peptide Chemistry (2012), TheBiopolymers Murray Goodman Memorial Prize (2012), The ProteinSociety Emil Thomas Kaiser Award (2011), The American PeptideSociety Rao Makineni Lectureship Award (2011), The AmericanPeptide Society Vincent du Vigneaud Award (2008) and The AmericanChemical Society Arthur C. Cope Scholar Award (2001).

Kelly cofounded FoldRx Pharmaceuticals based on his research and subsequent formulation of Tafamidis to treat familial amyloidpolyneuropathy. This first-in-class drug is the first pharmacologic agentthat halts neurodegeneration in a human amyloid disease. Tafamidis (or Vyndaqel®) also provides the first pharmacologic evidence that the process of amyloidogenesis causes the degeneration of post-mitotictissue. He also cofounded Proteostasis Therapeutics, a company thatuses small molecules to alter the protein homeostasis network toameliorate several aggregation-associated degenerative diseases.

“Biological and Chemical Approaches to Adapt Proteostasis toAmeliorate Protein Misfolding and Aggregation Diseases”The cellular protein homeostasis, or proteostasis network, regulatesproteome function by controlling ribosomal protein synthesis, chaperone-and enzyme-mediated protein folding, protein trafficking, proteindegradation and the like. Stress responsive signaling pathways matchproteostasis network capacity with demand in each subcellularcompartment to maintain cellular homeostasis. The beginning of thepresentation will focus on how the proteostasis network can be adaptedthrough unfolded protein response arm-selective signaling to alleviateseveral loss-of-function diseases where excessive misfolding anddegradation leads to maladies like the lysosomal storage diseases. Thesecond part will focus on how the proteostasis network can be adaptedthrough heat shock response activation to alleviate aggregation-associated degeneration of post-mitotic tissue in Alzheimer’s and relateddiseases. The third part of the talk will focus on a chemical strategy toachieve protein homeostasis, wherein small molecule kinetic stabilizersproduced by structure-based drug design are employed to halt theprogression of peripheral neuropathy in the human disease familialamyloid polyneuropathy linked to transthyretin amyloidogenesis. Kellywill explain how delineating the molecular mechanism of transthyretinaggregation linked to pathology led to a regulatory agency-approveddrug. The last part of the talk will focus on what has been learnedabout the etiology of these diseases vis-à-vis a successful clinical trial.

Dr. Bonnie L. Bassler is a member ofthe National Academy of Sciences and theAmerican Academy of Arts and Sciences.She is a Howard Hughes Medical Institute(HHMI) investigator and the SquibbProfessor of Molecular Biology at Princeton University. Bassler received a BS in biochemistry from the University of California at Davis and a PhD inbiochemistry from Johns HopkinsUniversity. She performed postdoctoral

work in genetics at the Agouron Institute and joined the Princetonfaculty in 1994. The research in her laboratory focuses on themolecular mechanisms that bacteria use for intercellularcommunication — a process called quorum sensing. Bassler’s researchis paving the way to the development of novel therapies for combatingbacteria by disrupting quorum-sensing-mediated communication.

At Princeton Bassler teaches undergraduate and graduate courses.She directed the Molecular Biology Graduate Program from 2002 to 2008and chairs Princeton University’s Council on Science and Technology.

Bassler was awarded a MacArthur Foundation Fellowship in 2002.She was elected to the American Academy of Microbiology in 2002 andbecame a fellow of the American Association for the Advancement ofScience in 2004. She was given the 2003 Theobald Smith SocietyWaksman Award and is the 2006 recipient of the American Society forMicrobiology’s Eli Lilly Investigator Award for fundamentalcontributions to microbiological research. In 2008 Bassler was givenPrinceton University’s President’s Award for Distinguished Teaching.She is the 2009 recipient of the Wiley Prize in Biomedical Science forher paradigm-changing scientific research. Bassler is the 2011recipient of the National Academies’ Richard Lounsbery Award and isthe 2012 UNESCO-L’Oreal Woman in Science for North America.

Bassler was president of the American Society for Microbiologyfrom 2010 to 2011 and is the chair of the American Academy ofMicrobiology Board of Governors. President Barack Obamanominated her for membership to the National Science Board. Basslerwas an editor for Molecular Microbiology; she is currently editor ofmBio, chief editor of Annual Review of Genetics, and an associateeditor for Cell, Journal of Bacteriology, Proceedings of the NationalAcademy of Sciences and other journals.

“Manipulating Quorum Sensing to Control Bacterial Pathogenicity”Cell-cell communication in bacteria involves the production, release andsubsequent detection of chemical signaling molecules called autoinducers.This process, called quorum sensing, allows bacteria to regulate geneexpression on a population-wide scale. Processes controlled by quorumsensing are usually unproductive when undertaken by an individualbacterium but effective when undertaken by the group. For example,quorum sensing controls bioluminescence, secretion of virulence factors,biofilm formation, sporulation and the exchange of DNA. Thus quorumsensing allows bacteria to function as multicellular organisms. Bacteriamake, detect and integrate information from multiple autoinducers, someof which are used exclusively for intra-species communication, whileothers enable inter-species communication. Research is now focused onthe development of therapies that interfere with quorum sensing tocontrol bacterial virulence.

Speakers

Dr. Holger Sondermann is anassociate professor in the Department ofMolecular Medicine at Cornell Universityand director of graduate studies for thepharmacology program at Cornell. Inaddition, he is involved in teachingundergraduates and students enrolled inthe doctor of veterinary medicine program.

Sondermann received his degree inbiology from the University of Cologne,Germany, and a PhD in biochemistry for

his studies conducted at the Max Planck Institute of Biochemistry,Martinsried, Germany. He performed postdoctoral work in structuralbiology and biophysics with Dr. John Kuriyan, first at RockefellerUniversity and then at the University of California, Berkeley. Hejoined the Cornell faculty in 2005 and was the Robert N. Noyce Assistant Professor in Life Sciences and Technology.

Research in the Sondermann laboratory focuses on two mainareas: bacterial signaling controlling biofilm formation and membranetrafficking in eukaryotes. His group is interested in deciphering thebasic regulatory principles in signal transduction networks on amolecular level using a combination of x-ray crystallography,biophysical and cellular approaches.

Sondermann was a Pew scholar in the biomedical sciences and won the Pfizer Animal Health Award for Research Excellence in 2010. He serves on the Research Council of Cornell University’sCollege of Veterinary Medicine and on review panels for the NationalInstitutes of Health.

“The Ins and Outs of c-di-GMP Signaling in Bacterial Biofilm Formation”A small intracellular signaling molecule, c-di-GMP has emerged as acentral regulator of bacterial physiology, regulating the formation ofcollaborative biofilm communities on one hand, and motility andvirulence of planktonic cells on the other. Recent structure-functionstudies have shed light on the mechanisms of c-di-GMP turnover andsensing. Synthesized and degraded by diguanylate cyclases andphosphodiesterases, respectively, c-di-GMP regulates the function ofan impressive array of structurally and functionally diverse effectorprotein modules. In this presentation, Sondermann will focus on themolecular mechanisms that yield finely tuned signaling cascadescontrolling cell adhesion in several bacterial species. In the long term,the results emerging from these studies could provide blueprints forthe development of novel therapeutics against bacterial infections.

Dr. Basil Rigas is a professor ofmedicine and the William and Jane KnappProfessor of Pharmacology at StonyBrook University. He received his MD and DSc, both with highest honors, fromthe University of Athens and trained ininternal medicine at Brown University,gastroenterology at Yale University andbiochemistry at Brandeis University. Heheld faculty positions at CornellUniversity, Rockefeller University and

the American Health Foundation. Until recently, he was the chief ofthe Division of Gastroenterology at Stony Brook. Rigas now servesin the Stony Brook University School of Medicine as vice presidentfor Business Development, dean for Clinical Affairs and director ofCancer Prevention.

Rigas pioneered the application of infrared spectroscopy to thestudy of cells and tissues; he established its potential in cancerdetection, for which he holds numerous patents. His currentresearch is focused on cancer prevention, with emphasis on thedevelopment of novel anticancer agents.

“Modified NSAIDS and Cancer”Cancer chemoprevention has emerged as a promising approach tocancer control. Epidemiological studies and interventional trials haveestablished NSAIDs as efficacious chemopreventive agents againstseveral human cancers. Their drawbacks are low efficacy andsignificant side effects. To overcome these limitations, Rigas hasdeveloped a general approach through which targeted chemicalmodifications of NSAIDs enhance their efficacy and minimize theirtoxicity. Using various preclinical models, he has demonstrated thatmodified NSAIDs, alone or in combination with other agents, achievestrong chemopreventive efficacy against various cancers, reaching insome cases 100 percent; particularly responsive cancers include thoseof the lung, colon, breast and skin. The formulation of modifiedNSAIDs in nanocarriers shows great promise as a mode of theirdelivery to cancer cells. The safety profile of modified NSAIDs hasbeen excellent. Mechanistically, the dominant mode of action ofmodified NSAIDs is the induction of oxidative stress, which leads to a profound cytokinetic effect in the target tissues. Suppression of the thioredoxin system, mainly of thioredoxin reductase, underliesmuch of the redox effect of these compounds.

Speakers

Dr. Deborah Hung is a physician-scientist at the Broad Institute of MITand Harvard, the Department ofMolecular Biology at the MassachusettsGeneral Hospital and the Department ofMicrobiology and Molecular Genetics atHarvard Medical School. She receivedher PhD in organic chemistry fromHarvard University under StuartSchreiber and pursued her postdoctoralresearch under John Mekalanos at

Harvard Medical School. Hung is combining chemical biological and genomic approaches

to define host-pathogen interactions and to reveal essential in vivogene functions of pathogens to explore new paradigms for anti-infective intervention. By deploying small organic molecules andgenome-wide tools to both perturb and understand bacterialinfection, she is working to provide insight into new approaches to avariety of devastating pathogens, including Vibrio cholerae,Pseudomonas aeruginosa and Mycobacterium tuberculosis.

“Chemical Biological Approach to TB: Identifying New Drug Targets”There is an urgent need for new drugs to treat tuberculosis (TB),particularly in the setting of rising drug and multi-drug resistance inM. tuberculosis. One of the major challenges of anti-TB drugdiscovery has been the identification of novel, validated in vivotargets that can be chemically disrupted, thus bearing truetherapeutic potential. New molecules that hit novel targets invalidated pathways have the dual advantage of a high likelihood oftherapeutic efficacy based on a validated mechanism of action whileovercoming the high levels of resistance to current inhibitors of thepathway. These factors immediately elevate the chemical class andtarget above the majority of other possible candidates, few as theyare for TB, in potential for therapeutic development. Hung willdiscuss her efforts taking this type of strategy.

Dr. Elizabeth Boon received her ABwith highest honors in chemistry fromKenyon College in 1997 and her PhD from the California Institute of Technologyin 2003. She completed a National Institutes of Health PostdoctoralFellowship at the University of California,Berkeley, before starting at Stony BrookUniversity in fall 2006.

Boon has received several awards forher research, including the Presidential

Early Career Award for Scientists and Engineers, the AmericanChemical Society PROGRESS/Dreyfus Lectureship Award, theNYSTAR Watson Young Investigator Award, the Office of NavalResearch Young Investigator Award and the Rising Star Award fromthe Research Foundation of the State University of New York. In2011 the Kavli Foundation and the National Academy of Scienceselected Boon a Kavli Fellow. Current research in her lab focuses ondetermining and characterizing the biochemical pathways responsiblefor regulating bacterial group behaviors.

“Nitric Oxide Signaling in Bacteria: Discovery of a New Mechanismfor Regulating Bacterial Group Behavior”The ability of biological systems to sense and respond to externalstimuli is of fundamental importance. Dissolved gases such as nitricoxide (NO), carbon monoxide and molecular oxygen are increasinglyrecognized as important biological signals. NO is a well-knownsignaling molecule in eukaryotic organisms, regulating processessuch as vasodilation and neurotransmission. Recent evidenceindicates that NO also serves a signaling role in bacteria; NOsignaling has been implicated in processes such as quorum sensingand biofilm formation. Biofilms are surface-bound, matrix-encapsulated, multicellular communities that are extremelyresistant to antibiotic treatments. In addition to being important inmany naval, industrial and environmental processes, biofilms areresponsible for approximately 60 percent of all human infections.Despite the well-documented role of NO in this process, themechanism for NO regulation of biofilm formation has not beenestablished. Boon hypothesizes that the NO/H-NOX signalingpathway may contribute to biofilm regulation. H-NOX domains areevolutionarily conserved gas-sensing heme domains that include thewell-characterized eukaryotic NO sensor, soluble guanylate cyclase.In the genomes of bacteria, H-NOX genes are typically co-cistronic with either a diguanylate cyclase (DGC) or histidinekinase (HK) gene. Both DGCs and HKs are linked to biofilmregulation. Evidence from biochemical and biophysicalcharacterization of proteins in the H-NOX signaling pathway aswell as proteomic, genetic and growth studies will be presented tosupport this hypothesis.

Speakers

Dr. David Lawrence is the FredEshelman Distinguished Professor at theUniversity of North Carolina at ChapelHill. He is a professor of chemistry,chemical biology and medicinal chemistry(in the School of Pharmacy), pharmacology(in the School of Medicine) and is aninvestigator in the Lineberger CancerCenter. He maintains two labs, one in theDepartment of Chemistry and the other ina combined facility that houses labs from

the Schools of Medicine and Pharmacy.Lawrence earned his BS degree in biological sciences from the

University of California at Irvine, where he conducted undergraduateresearch in the laboratory of Harold Moore from the Department ofChemistry. He went on to graduate studies in chemistry at UCLA andearned his PhD with the late Professor Robert Stevens in the generalarea of total synthesis. His postdoctoral studies were conducted withthe late E.T. Kaiser at The Rockefeller University and focused on thedesign and construction of chemically altered enzymes possessing newcatalytic activities.

Lawrence assumed his first faculty position in 1986 at the StateUniversity of New York at Buffalo in the Department of Chemistry.His rose through the ranks to full professor and moved to the AlbertEinstein College of Medicine in 1996 as a professor of biochemistry. Hehas been a faculty member at the University of North Carolina since2007, and is chairman of the Department of Chemical Biology andMedicinal Chemistry in the School of Pharmacy and co-director of theuniversity-wide chemical biology graduate program. His externalprofessional activities include service on the editorial board of Accountsof Chemical Research and on the Macromolecular Structure andFunction E Study Section at the National Institutes of Health. He isalso co-organizer of the 23rd American Peptide Symposium, which willbe held in Hawaii, June 22 to June 27, 2013.

Lawrence’s work is focused on the development of chemical probesfor deciphering the action and function of signaling pathways. Theseagents include inhibitors, sensors and activators of signaling proteins aswell as light-activatable species, which are used to examine thespatiotemporal elements associated with intracellular biochemicalpathways.

“Organic Chemistry at the Edge of Biology: Taming Cell BehaviorWith Light Responsive Molecules”Biological systems are characterized by a level of spatial andtemporal organization that often lies beyond the grasp of present-day methods. Light-modulated bioreagents can be introduced intocells in an inactive form and subsequently “switched on” using light,thereby allowing the investigator to probe, perturb or samplebiological phenomena at a time and/or place of his/her own choosing.Lawrence will describe the challenges associated with the design,synthesis and use of light-responsive bioreagents; present the scopeand limitations associated with the instrumentation required fortheir application; and provide a few recent examples used toscrutinize the secrets of cell signaling and behavior.

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promotion of Stony Brook University and/or Stony Brook Medicine.

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AcknowledgmentsCHEM-MASTER INTERNATIONAL INC.

FOREST LABORATORIES INC.

DEPARTMENT OF CHEMISTRY, STONY BROOK UNIVERSITY

OFFICE OF THE VICE PRESIDENT FOR RESEARCH, STONY BROOK UNIVERSITY

SCHOOL OF MEDICINE, STONY BROOK UNIVERSITY

Stony Brook University/SUNY is an affirmative action, equal opportunity educator and employer. This publication can be made available in alternative format upon request. 12080216

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Institute of Chemical Biology&Drug DiscoveryICB&DD