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Structural Biology Expertise
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A publicly listed integrated global pharmaceutical & life sciences company
Jubilant Life Sciences revenue for FY’18 $ 1,165 million
Jubilant Life Sciences – An Integrated Global Life Sciences Company
Drug Discovery and Development Solutions• Drug Discovery Services
• Development: GMP and Non-GMP NCE supply
• Integrated Discovery Collaborations
• Proprietary Innovation Assets for out-licensing
• Machine Learning
Life Science Ingredients
Specialty Intermediates• Advance Intermediates• Fine Ingredients• Crop Science IngredientsNutritional Products• Vitamins• Animal Nutrition
Life Science Chemicals • Life Science Chemicals• Ethanol & Specialty Gases
Pharmaceuticals
Generics• API’s • Dosage Formulations • Indian Branded PharmaceuticalsSpecialty Pharmaceuticals• CMO-Sterile Injectable • Radiopharmaceuticals• Allergy Therapy Products
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Company
Employees
Customers
Founded in 2000; subsidiary of Jubilant Life Sciences
Global top-10, mid-sized, virtual pharmaceutical and biotech companies
750+ employees. Most PhDs have >10 years of US/EU experience
Jubilant Biosys Solutions- Innovation Driven CRO & CDMO
Integrated discovery capabilities from target to clinical candidate and Digital
Drug Discovery ServicesPre-clinical Chemistry capabilities
including GMP and Scale-up
Track Record Delivered over 75 integrated projects
Bangalore, India Noida, India
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Target to Lead Generation
Lead Optimization Candidate Selection (IND)
Structural Biology (Protein Science, Crystallography) Medicinal and
Computational Chemistry Screening & Profiling Early ADMET & PK In vitro / In vivo
Pharmacology
Medicinal Chemistry DMPK SBDD (Co-crystallization,
Computational Modelling) Target Engagement &
Disease Models Safety Profile Pre-formulation
Integration of Discovery Process Designed for Speed
Process Development Scale-up & GMP API
Supply Genotox Non-GLP & GLP Tox D2M Predictions
(WinNonlin)
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Gained experience through a broad portfolio of programs which drive successful outcomes
Target to Hit Ph I / IIHit to Lead Lead Op Candidate IDTV
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Non Enzymatic
Enzyme
GPCR
Kinase
Disease Biology Expertise
Oncology Metabolic Disorder CNS Pain & Inflammation (P&I)
20 + Programs
15 + Programs
15 + Programs
15 + Programs
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Why Jubilant Biosys?
A highly experienced scientific team; delivered >75 integrated discovery programs
New technologies applied to accelerate drug discovery and improve decision-making quality
A boutique CRO with a talented team of >550 scientists giving your program priority
Investing in the future of drug discovery and development through expansion
Leadership with global pedigree in US, EU and Japan
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“We share your passion of Drug Discovery & Development”
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JDDS Flexible Business Models made for SpeedSustainable Innovation & Outcomes to Our Clients
Build to alignSolutions
Integrated DiscoverySolutions
Proprietary Innovation for
Licensing
Discovery, Preclinical & Clinical Solutions (FTE / FFS)
Medicinal & Synthetic Chemistry, Structural Biology, Molecular Modeling, Discovery Biology, Pharmacology, Bioinformatics, Bio analysis, Toxicology, Scale-up, cGMP
Jubilant Shared risk for Integrated Drug Discovery Programs
Focused across therapeutic areas– Oncology, CNS , MD and P&ITarget to Preclinical Candidate, Candidate to POC
Jubilant Innovation for Licensing / Partnerships
Proprietary drug discovery programs funded by Jubilant to create small molecule assets (up to IND) to be partnered or licensed
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Structural Biology – Proven expertise in Protein Structure Determination
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Biophysical characterization :- DSF/TSA carried out in-house ; CD, DLS, MS, BLI, SPR are outsourced;
In-house X-ray Diffraction Facility
Highlights• Multi construct approach for structural studies• E. coli, Insect cell (Baculovirus) & Mammalian expression systems • Co-expression, limited proteolysis, deglycosylation skills• In-house X-Ray facility & access to Synchrotron (Australia)• Supported multiple discovery programs by co-crystal structure determination• Composite team of well experienced Ph.D and MS scientists• Demonstrated expertise in protein chemistry & structures
Recent Publications: Crystal structures of monkey and mouse NNMT bound with end product, 1-methyl nicotinamide. BBRC. 2017 Sep 16;491(2):416-422.A small molecule inhibitor of Nicotinamide N-methyltransferase for the treatment of metabolic disorders; Sci Rep. 2018 Feb 26;8(1):3660;
• ExpertiseAssay gradeBiophysical gradeCrystallization grade
> 300 proteins > 100 targets (different target classes)• Culture capacity
E. coli - 60-80 L/ weekBaculovirus– 24 L/ weekMammalian– 4-6 L/ week
Proteins
~10 Novel structures~ 250 co-crystal structures~ 50 targetsTarget classes :Kinases, Phosphatases, Proteases, Deaminases, Lyases, Isomerases, Carboxylases, Dehydrogenases, PDEs, Epigenetic targets, Chaperone, Apoptosis protein, Interleukins & receptors, andOncogenic transcription factors
Structures
• Cell linesCHOHEK293HEK293SFreedom CHO-S
• Stable cells and Characterization* Plasmid mediated expression* Viral mediated expression
Functional characterization
Cell Line Engineering
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Infrastructure
Cloning & Expression Protein Production Protein
Characterization Crystallography
• Thermocyclers• Real Time PCR• Gel doc system• Transilluminators• Spectrophotometers• Deep freezers• Sonicator• Centrifuge • Biosafety hoods• Cedex cell counter• Shakers• Incubators • Wavepod• Reach-in CO2
incubator
• Centrifuge • Ultracentrifuge • AKTAs • Walk-in cold rooms• TFF
• Polaroid Microscopes• Walk-in cold rooms• X-ray Diffraction
Facility• Micromax 007HF
generator• VarimaxHR optics• Mar345dtb detector• Oxford cryo system
• Crystallization at varied incubation temperature (4°C -22°C)
• SDS-PAGE• Immunoblotting• Activity
measurements• Thermal Shift assay
(TSA or DSF)• Endotoxin
detection/removal • Mass Spec. analysis*• Protein ID by tryptic
digestion + MS*• Biacore/Octet*• CD/ITC*
* In collaboration with Indian Institute of Science, Bangalore
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Protein Expression Capabilities
E. coli Baculo-insect Mammalian
Strains
T7 promoter Expression strains:
BL21(DE3)BL21(DE3)pLysSRosetta2(DE3)Rosetta2(DE3)pLysSBL21(DE3)AIT7 express
Tac promoter expression strains:
Novablue & Top10
Sf9Sf21 Hi5
CHOHEK293HEK293sFreedom CHO-S
Co-expression
Chaperone: groES, groEL, tigProteins: regulatory domain, phosphatase etc
Regulatory domain
Cell Culture capacity 60-80 liters/week 24 liters/week 4-6 liters/week#
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# Scale up to 5L in wavebag using wavepod
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Thermal Shift Assay Capabilities
• Assist protein purification (Optimal buffering pH, Additives, Salts)
• Storage buffer optimization
• Crystallization buffer optimization
• To analyze aggregation / improper folding in proteins
• Screen protein variants to check stability upon mutations
• Analyze small molecules binding
• Protein – protein complex
• Antigen –Ab binding
• Filtering compounds for crystallization based on positive Tm shift
Ligand ScreeningProtein Stability Screening
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35373941434547495153555759616365
RFU
10^
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Temperature (°C)
Melt Curve of Protein in presence of Compound
10 uMTm=57°C
PositiveTm=51°C
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Collaborations carried outside Jubilant
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Activity Service Provider Time lines CDAin place
Primers/DNA Sequencing Eurofins, Bangalore 1 -2 weeks Yes
Synthetic genes GenScript, Hong Kong &GeneArt (now part of Life technologies or TFSL)
3-4 weeks Yes
Biophysical Characterization: Mass Spec, SPR, DLS, ITC
Indian Institute of Science, Bangalore
1 week Yes
*Synchrotron Data Collection Australian Synchrotron Facility, Australia
Flexible in reserving beam slot
Yes
*Based on the need we also work with other Synchrotron centers: Diamond Light Source, UK as well make use of clients beam time.
Note: Samples goes outside Jubilant are all masked and all scientists involved in the project signs CDA
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Case Study G2S - Delivered Co-crystal Structures of Kinase
• Multi construct approach (gene boundaries & mutants) in bacterial and insect cell expression system
• Impacted the client program in obtaining potent & selective inhibitor through SBDD• Milestones achieved
To provide ligand bound structure for a protein for which published structure is not amenable for bound structureObjective
Gene expression constructs, crystallizable grade proteins and ligand bound structuresDeliverables
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Optimized Purity
Complete Dephosphorylationaddressed non-homogenity
Diffracting Quality Crystal Crystal Structure (2.4Å)
32900 33000 33100
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Case Study G2S – SBDD Support for Integrated Drug Discovery Programs
• Selectivity achieved for Kinase X & Y over Kinase Z• Enabled achieving 2 integrated discovery milestones
To support integrated program with bound structures to identify novel small molecule dual inhibitor against Kinase X and Kinase Y
Objective
Expression constructs, crystallization grade protein and Ligand bound structures of Kinase X and unrelated Kinase ZDeliverables
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1 2 3
Kinase XIC50 (µM) 0.003 0.020 0.006
Kinase Y IC50 (µM) 0.042 0.092 0.023
Kinase ZIC50 (µM) 0.0005 0.264 0.211
Gate keeper modifications
Challenge: Selectivity issues with dual inhibitors for unrelated Kinase Z
Kinase X Kinase Z Compound
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Case Study G2S – Novel Structure Determination ofHuman Deaminase Enzyme
• Multi construct approach• ~2.3Å diffracting crystals• Supported SBDD – Integrated Program
To determine ligand bound structure of a human deaminaseObjective
Gene expression constructs, crystallizable grade proteins and Apo & ligand bound structure Deliverables
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• No Structure in public domain
• Poor Yield
Challenges : Optimized insect cell expression and purification
Robust crystallization for soaking (by tweaking with additives)
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Case Study G2S – Novel Structure Determination of BIR domain of XIAP (apoptosis family of proteins)
• Multi construct approach designed based on NMR structure• Apo structure at 1.85Å (in-house)• Client was able to reproduce the protocol at their facility
To determine structure of a BIR domainObjective
Gene expression constructs, crystallizable grade proteins and Apo & ligand bound structure Deliverables
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Roche-Jubilant together published in Acta. Cryst. D (2013) September edition (impact factor 14.1)
• Only NMR Structure is known• Client explored ~30 constructs• Challenge in concentrating protein
Challenges:
Optimized expression and purification
Supplemented with cofactor
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P2S: Fab & Fab: Peptide Complexes
• Scope: Solving 3D structures using client supplied Fab, peptides & proteins
• Client Samples• Fab• Peptides• Interleukin• Growth Factor
• Experimentation• Perform complexation by SEC• Crystallize or Co-crystallize• Collect data & solve structure
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Fab complexed with a peptide
Heavy chain
Peptide
Light chain
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Publications/Referrals of Jubilant’s Structural Biology
• The team’s expertise in Structural Biology is evident through the following joint publications, some with clients (Roche, Constellation) as well as referral by Pfizer & BMS
• Co-crystal structures of PTK6: with dasatinib at 2.24Å, with novel imidazo [1,2-a] pyrazin-8-amine derivative inhibitor at 1.70Å resolution. BBRC (2017) 482,1289-1295
• Crystal structure of the kinase domain of human protein tyrosine kinase 6 (PTK6) at 2.33Å resolution. BBRC (2016) 478, 637-642
• The structure of XIAP BIR2: understanding the selectivity of the BIR domains.Acta Cryst (2013) D69, 1717-1725
• Discovery, Design, and Optimization of Isoxazole Azepine BET inhibitors.ACS Med Chem Lett (2013) 4, 835-840
• Biophysical and Mechanistic Insights into Novel Allosteric Inhibitor of Spleen Tyrosine Kinase. J. Biol Chem (2012) 287, 7717-7727.
• Image Annotation and Database Mining to Create a Novel Screen for the Chemotype-Dependent Crystallization of HCV NS3 Protease. Cryst. Growth Des. (2011), 11, 1143-1151.
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Thank You for your Time
Our Values
For More Information:
Office and Research Sites:
Jubilant Biosys Limited#96, Industrial Suburb 2nd Stage, Yeshwantpur Bangalore - 560 022 Karnataka India.Tel. : +91 80 66628400
Jubilant Chemsys LimitedB-34, C Block, Sector 58, Noida, Uttar Pradesh 201301Tel: +91 120 409 3300