Integrated Services

Integrated Services
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Aurigene: Overview
Aurigene is a specialized biotech focused on
Oncology
Inflammatory disorders
 Fully integrated drug discovery infrastructure, >500 scientists
 Based in Bangalore, Hyderabad (India) and Kuala Lumpur (Malaysia)
Chemistry: Small Molecule and Peptide focused
Core technology strengths
SBDD (Structure based drug design): an effective & rational drug design toolbox guided by X-ray
crystallographic binding modes of small molecules (hit/lead) with target protein.
FBDD (Fragment based drug design): Aurigene’s TrugFragTM platform integrates biophysical and
computational methodologies for fragment based hit generation.
Business Model:
 Pioneer in a “collaborative drug discovery”model, built on leveraging strengths.
 Collaborative, Integrated and Standalone services.
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Aurigene: Overview
 Experience
20
• ~ 59 targets or programs
• Kinases, Proteases, Nuclear Hormone
receptors & non-GPCR membrane
proteins.
• 12 Partnerships in integrated discovery
(6 of the top 10 pharma)
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10
7
4
5
 Licensed multiple early-stage programs
 Track record
• 8 candidates nominated for IND filling.
• Two of most advanced candidates in
Phase-1 and Phase-2.
 Intellectual contribution
Aurigene scientists are inventors/co-inventors in 43 patent applications and 4 patent grants.
Integrated Services: Overview
Structural
Biology
Synthetic
Chemistry
Pharmaceutical
Development
Peptides
in vivo
toxicology
Medicinal
Chemistry
Molecular
Modeling
in vitro
biology
Biology
Scale up
in vitro
toxicology
ADME/PK
Analytical
R&D
in vivo
biology
Integrated Services
Customized
solutions
• Integrated Services: Medicinal Chemistry & Biology complement each other.
• Service offering : Target validation, Hit generation, Hit-to-lead & lead optimization.
• Leveraging Aurigene ‘s drug discovery Infrastructure and expertise .
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Integrated services: Key differentiators
 Ability to Integrate: Knowledge/best practices from discovery collaborations to bring
novelty to routine Medicinal Chemistry Services
 Successful track record:
• Focused at always achieving KPI’s/ SLA’s committed to the partner; evident from the
strategic partnerships with several large and mid-pharma companies
• Average tenure of Collaborations ~3 years
• Collaborations have scaled up with several partners doubling the FTE count over the
last 5 years
Experienced Team:
• Average industrial experience of bench level chemist ~7 years
• Average tenure of middle management personnel ~6 years
Secured IP and IT infrastructure:
• All projects are secured in terms of IP through need-only IT access to project related
information/data and periodic trainings.
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Chemistry
Infrastructure and Capabilities
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Synthetic Chemistry
Infrastructure
 50 Modular chemistry labs; each fully equipped and self sufficient.
 5-9 fume hoods per lab and all essential instrumentation
 Biotage Microwave, Combi-flash MPLC systems
 Parr Shaker, Ozonator, Auto Claves
 BOHDAN blocks & Buchi Syncore Parallel Synthesizer
 Scifinder/Reaxys/ Online journals: Access to every chemist.
Expertise
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Route Scouting/Design to delivery support
Diversity oriented synthesis, multi-component reactions
Metal catalyzed reactions, “Click” chemistry,
Heterocyclic & carbocyclic chemistry
Asymmetric synthesis, Carbohydrate chemistry
Solid phase synthesis, Peptide chemistry
Focused libraries
Proven expertise and excellent track record with challenging
chemistry, multi-gram synthesis and focused libraries.
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Peptide Chemistry
Expertise

Linear and branched chain
 Derivatisation of peptides with Lipids,
 5 modular labs dedicated to peptide group
Steroids, Small molecules, Carbohydrate
 Synthesis : Manual & Symphony Automated
Peptide Synthesizer.
Conjugated peptides.
 Solid and solution phase synthesis capabilities
 Conformationally constrained peptides-
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Infrastructure
 Lyophilisers
Lactams, Multiple disulfides, Stapled
 Microwave reactor-Biotage Initiator
peptides
 Preparative HPLCs (4); Analytical HPLC (2), LC-MS
Labeling – Biotin; Fluorescein
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Peptide dendrimers
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Peptide based affinity ligands
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Peptidomimetics
2%
3%
2%
1% 1%
1%
5%
29%
5%
6%
One of the few drug discovery companies
in India with strong Peptide capabilities
18%
27%
Natural + Un natural AA
Branched Peptides
Lipidated Peptides
Lactam
Paptidyl resin
Disulphide / Nested
Stapled Peptides
Toxins
Labelled Peptides
Phospho Peptides
Pegylated
Head to tail Cyclization
Reagents for peptides
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Scale-Up
Infrastructure
Expertise
 Dedicated scale up, 20L reaction volume capacity
 Walk-in and low lying fume hoods
Scale up
NCEs
 20L rotary evaporator
 Kg level column purification facility
 Vacuum oven, High pressure autoclave
Alternative
synthetic
routes
Prodrugs &
Metabolite
synthesis
ScaleUp
Case studies
Intermediate
& scaffolds
Salt
selection
Polymorph
screening
Technology
transfer
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Analytical –R & D
Infrastructure
 NMR 200 MHz, 300 MHz, 400 MHz, 500 MHz,
600 MHz (Varian)
 LCMS API 2000 (Applied Biosystems)
 LCMS Single Quad (Agilent & Shimadzu)
 HPLC Analytical (Agilent1100 &1200)
Specialized capabilities
 Chiral and peptide purification using Diacel &
LUX ,CSP and C18 and C4 columns
 Support to GLP analysis for Tox studies
 Protein-ligand binding studies
 Stability studies
 Impurity profiling
 HPLC Preparative (Agilent & Shimadzu)
 UV & ELSD detectors
 Autotitrator (848Titrino Plus-Metrohm)
 FT IR (Spectrum One -Perkin Elmer)
 Polarimeter (Model 841 Perkin Elmer)
 Chiral HPLC columns
- Analytical (Chiralcel , Chiralpak, Lux
Amylose)
- Preparative (Chiralcel , Chiralpak, Lux
Amylose)
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Molecular Modeling
Infrastructure
Molecular Modeling
 CCDC’s state-of-the art docking platform
 ChemAxon modules- estimation of diverse molecular
properties, topology & geometry
 In-house developed tools for ADMET predictions
Ligand-based
approaches
Structure-based
approaches
QSAR
Molecular docking
Pharmacophore
modeling
Homology
modeling
Knowledgebased
Molecular
dynamics
 High-speed computing & 3D visualization facility
Expertise
 Virtual screening -Structure & Ligand based modeling approaches
Structural Biology
 Schrödinger suite-structure-based & ligand-based
modeling applications
 Ligand design-de novo, scaffold hopping, ligand hybridization,
fragment-linking & related techniques
 Database exploring & virtual library generation
 Macro-molecular modeling, molecular dynamics simulation
 QSAR & Pharmacophore-space modeling
 Predictive (in-silico) ADMET modeling
Support in SAR
optimization
Medicinal Chemistry
Wide range of computational and
creative expertise which complements
experimental data on structures
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Pharmaceutical Development
Infrastructure
 High Pressure Homogenizer (Micro-fluidics)
 Log P/pKA Analyzer
 Single crystal X-ray crystallography (Rigaku)
Capabilities
>50
Lead Opt to Candidate
nomination or safety phase
(preferred morph selection)
>15
Prior to Phase I and beyond
(comprehensive)
>5
GLP formulation
development &
support
Formulation development
>50
Support
>100
Salt screening
Lead ID to phase I
>10
Oral BA issues
Lead ID (early preclinical)
>50
Lead Opt to Candidate
nomination (Preclinical safety)
>50
Pre-CMC (to support candidate
nomination)
>20
Phase I enabling (to support
CMC/IMPD filing)
~5
Prior to phase I (Prototype for
FIH)
~5
 Thermo-Gravimetric Analyzer
 Tablet Compression Machine
Expertise
 Tox/IND enabling pharmaceutical developability
 Preformulation, Polymorph/salt selection
 Preclinical/Tox formulation & stability
 Excipient compatibility & selection
Pre-formulation
package
 API Stability Studies
 Prototype clinical drug product/stability
 Pre-CMC/CMC documentation
Track
Record
Lead ID phase (preliminary)
Polymorph propensity
assessment/screening
 Modulated-Differential Scanning Calorimeter
 Spray Dryer, Particle Size Analyzer
Discovery/Development phase
Formulation package
for phase I prototype
product
Proven track record/competencies in offering insights/solutions to developability of compounds &
generating data required for submission of IND
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Biology
Infrastructure &
capabilities
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Structural Biology
 150 Proteins expressed in Bacterial and Insect Cells
 300 Structures of different protein classes determined
with inhibitors
 In-house Rigaku Rotating anode RU300
Crystal structures of various target families
3.0-3.5 Å, 10
1.5-2.0 Å, 20
2.5-3.0 Å, 40
 Quick access to Synchrotron beamlines (APS, SLS,
ESRF)
2.0-2.5 Å, 80
Resolutions of the structures
Integrated gene-structure capabilities for supporting Structure-based Drug
Discovery
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ADME/PK
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Physicochemical properties
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• PK studies performed in mice, rats,
• Solubility and stability
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Drug Transport
• PAMPA, MDCK, Caco-2
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Distribution
• Protein binding
Metabolism and drug-drug interactions
• CYP Profiling, induction and inhibition
– Fluorescent and probe substrate
– Microsomes, S9, Hepatocytes
rabbits, guinea-pigs, hamsters and
dogs
Dose proportionality and multiple dose
studies
• Linear Pharmacokinetics of the NCE
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Excretion studies
• Major route of elimination of the
• Metabolic stability in
Rat/mouse/dog/human liver
microsomes or S9
Oral bioavailability
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NCE
Tissue distribution studies in rodents
Human dose and PK projection for FIM
studies
• Interspecies PK scaling by allometry
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Bioanalytical activities (An OECD - GLP
Accredited lab*)
Extensive range of ADME/PK and Bioanalytical Studies for generating
robust and reliable data for high quality drug candidates
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In vitro Screens: Assays & HTS Capabilities
Target Expertise
 Kinases
 Proteases
 Nuclear hormone receptors
 GPCRs
 Others: Dehydrogenases, nucleases,
phosphatases etc
HTS Capabilities
 Tecan Freedom EVO Liquid handling system
 Tecan Ultra Fluorescence Microplate Reader
• Steady state, Kinetics
• Luminescence
• Polarization
• Time Resolved Fluorescence
 Spectramax Gemini
• Detection in standard steady state
fluorescence and luminescence modes
Expertise in wide variety of efficacy screening assays (~50 biochemical & 36 cell
based - functional & mechanistic) that allow for screening of compound libraries
against specific validated targets and PD assays in cellular models for utilizing in
pharmacology
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In vivo Studies: Efficacy Models – oncology (1/2)
Syngeneic
and
metastatic
Xenografts with human tumor
cell lines
Origin
Cell line
Type
Breast
BT474, MDA-MB231
Subcutaneous and orthotopic
Colon
HCT-116, HT29
Subcutaneous
Lung
A-549, H1975
Subcutaneous
Ovarian
PA-1, SKOV-3
Subcutaneous
Prostate
PC-3, DU145, LnCap
Subcutaneous and orthotopic
Pancreatic
MiaPaca2
Subcutaneous
Melanoma
A375
Subcutaneous
Bladder
RT4
Subcutaneous
AN3CA
Subcutaneous
Epidermoid
A431
Subcutaneous
Myeloma
H929
Subcutaneous
Lymphoma
Ramos, Karpas 299
Subcutaneous and intravenous
Melanoma
B16F10 and F0
Subcutaneous
Breast
4T1
orthotopic
Kidney
Renca
orthotopic
Endometrium
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In vivo Studies: Efficacy Models – Inflammation (2/2)
COLITIS DTH
ARTHRITIS
ACUTE MODELS
Type
Animal Model
Species/ strain
Validation standard
LPS induced systemic inflammation
Female wistar rat
Roflumilast
LPS induced paw edema
Female wistar rat
Nimesulide
Carrageenan induced paw edema
Male wistar rat
Celecoxib
Carrageenan induced mechanical hyperalgesia
Male wistar rat
Celecoxib
Female C57BL mice
Kinase inhibitor
Collagen Induced Arthritis (Prophylactic)
Female Lewis rat
Leflunomide
Collagen Induced Arthritis (Therapeutic)
Female Lewis rat
Enbrel, Dexamethasone
Adjuvant Induced Arthritis (Prophylactic)
Female Lewis rat
Celecoxib
Male Lewis rat
Celecoxib
Female CD1 mice
Leflunomide
Male SD rat
Male SD Rat
Dexamethasone
Leflunomide
Female Lewis rat
Dexamethasone
Acute Arthus reaction
Medial Meniscus Induced Tear Osteo Arhritic model
DNFB induced contact dermatitis (Psoriasis)
Oxazolone induced contact dermatitis (Psoriasis)
Dextran Sulphate Sodium induced colitis
Trinitrobezene sulphonic acid induced colitis
Poised with Well established in vivo models to expedite Oncology &
Inflammation drug discovery and development initiatives
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In vitro Toxicology
In-vitro Toxicology
 Cytotoxicity in primary cells (hepatocytes)
 hERG functional Assay
• Electrophysiology using automated patch clamp
 Mutagenicity
• In-vitro - AMES Test
• In-vitro - Micronucleus Test
Robust in vitro Tox Assays to assess the potential genotoxicity of
compounds and support candidate selection
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In vivo Toxicology/Preclinical Safety: GLP & non-GLP
In vivo Toxicology: GLP
 Rodent Studies
• 4 weeks, 13 weeks, FOB
 GLP Certification
• Food and Consumer Products Safety Authority, The
Netherlands - 2003 & 2006
• National GLP Compliance Monitoring Authority, Indian GLP
Certification – 2004; Indian GLP Surveillance 2005 and 2006
• Complete (90% Support for 1st in man) Toxicology
Infrastructure
In vivo Toxicology: non-GLP
 Animals:
• Wistar rats
• Sprague Dawley rats
• Swiss Albino mice
 Route of administration: Oral, IV, IM, SQ, IP
 Tolerated dose determination – ATD, MTD
 Repeat dose toxicity
 Dose range finding study in Beagle Dogs, MTD study in Beagle
Dogs
Clinical Chemistry
Hematology
Operate in both GLP and non-GLP settings to generate complete toxicity
profile of compounds and analyze their safety
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Target Validation
Services
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Target Validation: Objectives & Deliverables
Objectives
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Replicate published findings to support the launch of a full-fledged discovery program
Establish druggability through small molecule/peptide approach
Confirm efficacy in relevant in vitro and in vivo models
Identify and validate PD markers in cellular models
Determine potential mechanism-based toxicity
Establish TPP
Devise differentiation strategies (in the case of fast follower programs)
Deliverables
 Synthesize sufficient quantities of mutually agreed tool compounds to support in vitro and in vivo
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studies
Express, purify proteins for biochemical assays and structural studies
Confirm feasibility of SGDD approaches and initial hit design strategies
Establish biochemical and cell based assays (mechanistic and functional) for potency
determination and in vitro validation
In vivo pharmacological validation including biomarker assessment ad potential mechanism
based toxicity
Objectives & Deliverables will be mutually agreed depending on the nature
of project
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Target Validation: Target to Tool compound
 Targets to be chosen by Collaborator
 Aurigene to pursue pharmacological validation; 9 to 12 months
 Decision criteria and program parameters to be defined
 Collaborator can choose to:
• Enter into a full fledged discovery Collaboration with Aurigene; if Program meets
the Defined criteria
• Drop the Program; if Program does not meet the Defined criteria
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Thank you!
www.aurigene.com
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© Aurigene Discovery
Technologies Limited.