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:

www.jubilantbiosys.combd@jubilantbiosys.com

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