NON-CONFIDENTIAL

Application of structure-based drug discovery to G protein-coupled receptors

Rob Cooke, SVP Biomolecular Structure

May 2019 | © Heptares Therapeutics Limited Disclaimer

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2 Agenda

1 Introduction to GPCRs

2 GPCR Platform and Discovery Examples

3 GPCRs and Immuno-Oncology

4 Summary

3 1

Introduction to GPCRs

4 G Protein-Coupled Receptors (GPCRs) Super Family

• Highly important family of drug targets in industry • 800 GPCRs including ~400 olfactory • 225 with known ligands, 150 ‘orphan’ receptors • Compelling biology across wide range of diseases • Many valuable yet challenging targets still untapped

Many Top-Selling Drugs Hit GPCRs ~ 30% of ALL prescription drugs

5 GPCR Targets as a Source of Drugs

FDA Drug Approvals FIC vs BIC GPCR Approvals

60 53 5% 50 45 3%7% 39 39 41 25% 36 3% 40 35 28 30 30 4% 27 26 27 30 24 24 4% 21 20 22 21 17 18 14 5% 20 11 11 8 5 7 5 5 5 5 6 10 3 3 2 4 4 4 4 4 3 3 10% 22% 0 12%

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 FIC PK Selectivity Polypharmacy Combination Toxicology CNS penetration Phys Chem Total GPCR Receptor kinetics Route Potency

• 116 GPCR targeted drugs over 20 year period (1995-2015) • Including 43 different GPCR targets • No decline in target class drug discovery success over time • 25% new GPCR targeting approvals were for first in class therapies • Majority of new GPCR approvals demonstrate improvements over existing agents (PK, selectivity & safety)

• However, many notable GPCR drug failures (efficacy & safety attrition) e.g. CB1 (obesity), CGRP (migraine), mGlu5 (Fragile X & depression), GPR40 (diabetes)

Source: Christopher et al. Med. Chem. Rev. 2018, 69

6 2

GPCR Platform and Discovery Examples

7 The Stabilised Receptor (StaR®) Key to our Structure-Based Drug Discovery (SBDD)

70

50

30 Drug 10 Candidates -10 -10 10 30 50 70

Unstable StaR Fragment X-ray Receptor Native Screening Crystallography Kinetics GPCR

• Native receptor spans cell membrane – highly unstable when removed

• Aggregates and loses function when purified

• 4-10 point mutations in GPCR stabilise it by 10-30ºC to create StaR®

• Stabilised receptor (StaR®) can be purified and retains function and shape

• StaR® is basis for integrated structure/chemistry/pharmacology platform

• 60+ Stabilised Receptors generated representing targets in agonist and/or antagonist conformations

8 Sosei Heptares Unique Stabilisation Platform Step-wise Receptor Engineering

• Step-wise stabilisation results in evolution of the receptor towards improved thermostability and recovery upon solubilisation • Process flexibility to “harvest” StaR® proteins for different purposes

9 StaR® Technology Reliably Delivers X-ray Structures Semi-automated scout purification of multiple constructs/conditions Crystals grown in lipidic cubic Milligram quantities of up to 6 proteins in 24 hours phase

S E C

Unstable StaR Express Membrane Solubilise Purify SEC LCP/VD Setup Crystals Optimise Structure Native GPCR

Screening: Fusions Positions Ligands Detergents

10 GPCR Structures Now Possible with High Resolution

• Excellent definition of ligand, side chains and waters at 1.7 Å resolution • Highest resolution GPCR structure solved to date

11 Now Applying Cryo-EM to GPCRs

Cryo-EM structure of the activated GLP-1 receptor in complex with G protein Zhang et al., Nature, 2017

Nobel Prize in Chemistry (2017) Current Opinion in Structural Biology, Volume 41, 2016, 194–202

• For many years cryo-EM images of proteins were limited to approx 7Å • Technical advances making use of direct electron detectors and new image processing techniques have revolutionised the field in the last 2-3 years • Structures have now been reported with 1.8Å resolution

Richard Henderson Joachim Frank Jacques Dubochet (glutamate dehydrogenase, 334kDa) and for a 64kDa particle “for developing cryo-electron microscopy for the high-resolution (hemoglobin, 3.2Å resolution) structure determination of biomolecules in solution”

12 X-ray Diffraction remains a Key Structural Engine

• Since 2010 we have solved >260 X-ray structures, from >25 different receptors

• In addition to driving our in-house Discovery efforts, these have led to several top quality publications and have been key factors in Pharma deals

GCGR CRF1 mGlu5 CCR9 PAR2 GLP1R C5aR

• X-ray diffraction will continue to be the engine behind our structure based design efforts, and our capabilities will advance, including moving towards soakable systems (for throughput) and free electron lasers (for smaller crystals)

13 Hit Generation: Novel Assay Screening Platforms Ligand-independent thermostabilisation • Frequent absence of suitable ligands drove development of alternative assay platforms that do not require ligand binding to measure protein stability • Receptor aggregation linked to fluorescence read-out • Compatible with crude lysate and high throughput screening of mutants • Developed further as a thermal shift assay to enable fragment screening, orthogonal hit validation, active enantiomer screening and binding site mapping

14 Hit Generation: SPR Fragment Screening Platform H N • SPR screening with AR 1 A as counter screen β 2A N

β1 • Several related hits F Control F F β Hits 1 KD = 16 µM Caffeine LE = 0.41

A2A A2A Hits Control Typical results for ‘well behaved’ hits

A2A

H H N H N N

N N KD = 16 µM Ki = 224 nM N Ki = 68 nM LE = 0.41 N LE = 0.53 LE = 0.65 F N F H F

Source: Christopher et al. J. Med. Chem. 2013, 56, 3446 15 Hit Generation: In Vitro Pharmacology Establishing invitro assays to support primary hit identification

Building platforms to support hit ID on a target by target basis

Library hit ID visualisations Visualisation tools integrated to enable hit identification 1. Generation of high throughput in vitro assays to and selections for follow-up support HCS fragment screening and profiling of VS libraries. • Assays established for both functional (potency/efficacy) and competition binding (affinity) in either 96 well or 384 plates Inhibition n=1 n=1 Inhibition • Generation of frozen cells expressing target where possible to support consistency and flexibility • Large scale membrane preparations generated for competition binding studies Inhibition n=1 • Maximise hit identification through use of stabilised proteins to build unique invitro assay platforms in parallel with SPR biophysics CADD: Virtual screening and ligand design methods Structure-sequence analysis and mutation study design group (see next slide) 2. CADD input • Structure-based and ligand-based VS and ligand design • Review of StaR Tm mutagenesis data for model optimisations • Key residue predictions for invitro testing

16 Virtual Screening and Computer-Aided Drug Design Approaches Working with Chemistry and Pharmacology to identify hits and design novel ligands

Development and application of VS and CADD methods Shape/pharmacophore screenings Docking and Structural protein-ligand Interaction Fingerprint scoring

1. Virtual Screening • Ligand-Based (LB): Chemical FP similarity (incl. GPU similarity for rapid search of trusted vendor collection, Enamine REALdb, combinatorial/de novo library design), Ligand pharmacophore/shape similarity (e.g. ETKDG/Omega2- ROCS/AlignIT, BROOD) • Structure-Based (SB): Docking (Glide), combining energy-based and structural Interaction Fingerprint scoring and post-processing, pharmacophore/IFP similarity based 2. Computer-Aided Drug Design GRID/WaterFLAP/waterMAP GPCR binding site analysis In-house MedChem Ideas algorithm for library design • Customised combinatorial and de novo library design (e.g. in-house MedChem Ideas, LB/SB/MMP based isosteric replacements), initiating novel AI driven approaches (DRL, RNN, GAE) and integrated molecule generation and retrosynthetic analysis tools. • In-house GRID, waterFLAP, waterMAP analysis and GPCR customised MD based binding kinetics prediction (aMetaD) and FEP+ simulation protocols to guide SBDD (w. Molecular Discovery, Schrodinger) aMetaD – Solvation Factor FEP+ cycle • LiveDesign + 3D brainstorm sessions (Vida) for data integration, analysis, and LiveDesign collaborative ligand design efforts across project team(s), facilitated by customised ligand property prediction, automated docking (MCS, reference ligand similarity based target selection), customised GPCR-ligand complex visualisation.

17 Lead Optimisation Example: mGlu5 Receptor NAM

O Cl CN Cl CN

N O N H H N F HO N N N N N N Fragment N N Advanced N N X-ray driven N Screen homology SBDD F modelling mavoglurant HTL14242

mGlu5 pKi 8.0 mGlu5 pKi 5.2 mGlu5 pKi 9.3 mGlu5 pKi 9.3 clogP 3.1 clogP 1.1 clogP 2.6 clogP 3.0 LE 0.47, LLE 4.9 LE 0.40, LLE 4.1 LE 0.60, LLE 6.7 LE 0.57, LLE 6.3 CNS MPO 5.2 CNS MPO 5.5 Acetylene containing Novel non-acetylene Significant LLE & LE Good PK Poor PK (rat F 22%) containing chemotype enhancements (F%>80% - 2 species) Sub optimal potency Sub optimal High RO & LLE metabolic stability (ED50 0.3 mg/Kg) Clean off-target profile

HTL0014242 Phase 1 clinical study 2019 - Double blind placebo controlled single ascending dose in healthy volunteers

Source: Christopher et al. J. Med. Chem. 2015, 58, 6653

18 Glutamate & mGlu in ALS 5 G93A Amyotrophic Lateral Sclerosis Summary of mGlu5 effects in the SOD1 model • Glutamate-mediated toxicity is recognised as a HTL0014242 HTL0014242 Readouts Vehicle Riluzole mechanism of neuronal injury 25D Cohort 75D cohort • Glial cells reduced capacity to uptake glutamate

• Increased glutamate receptor expression post- Effect on onset of clinical signs of disease ✕ ✕ - - synaptically

• Also evidence of neuroinflammation – activation Increased number of motor neurons at 90D ✕ ✕ ✓ - of glial cells (astrocytes and microglia)

Reduction in GFAP staining at 90 days in SC ✕ ✓ ✓ ✕ mGlu5 expression in ALS spinal cord glia correlated with markers of glial

activation (GFAP) Reduction in Iba1 staining at 90 days in SC ✕ ✓ ✓ ✕

Improvement in motor function as seen on • Partial knockdown of mGlu receptor increases - 5 rotarod ✕ ✕ ✓ motor performance and survival in mouse models (Bonficino et al., 2017) Effect on survival ✕ ✕ ✕ -

Source: Shaw P., BMJ vol 318; 1999; Bonficino et al., Neuropharmacology vol 123; 2017

19 Finding new Allosteric Binding Sites using StaRs

Family A CRF ligands 1 C-C chemokine Receptor Receptor type 9 Hollenstein et al. TM7 Oswald et al., TM5 Nature (2013) TM6 Nature (2016)

Deep allosteric site Intracellular site

Glucagon Receptor Protease-Activated Jazayeri et al., Receptor 2 Nature (2016) Cheng et al., Extra-helical site Nature (2017) 21 Intra-helical and extra-helical allosteric sites

20 Hit Generation Example: PAR2 Receptor Antagonist Discovery

• Collaboration with AZ, N-ter AZ8838 TM4 ECL2 fragment and HTS TM5 TM3 screening ECL3 ECL1 • Antagonists inhibit peptide and protease activation of the receptor TM6

OH H N • Difficult to optimise in the TM7 N F TM1

absence of structural TM3 TM2 AZ'8838 understanding TM4 TM1 TM5 • Binding site identified in TM6 TM7 PAR2 X-ray structure C-ter

• AZ8838 completely buried Helix8 in a small binding pocket, ICL1 lined by residues from ICL2 TM1-3, TM7, ECL2

Cheng et al. Nature, 2017

21 Hit Generation using DELT for PAR2 PAR2 in Complex with X-Chem Hit AZ3451

N-ter • X-Chem DNA encoded library technology AZ3451 TM6 ECL2 TM7 ECL3 TM5 TM1

TM6 TM5 ECL1 TM4 TM3 • Binding hits - confirmed as functional N TM3 O Br NH N antagonists of PAR2 receptor TM7 O N O TM2

• AZ3451 binds in novel extra-helical site AZ3451 • Interaction with PAR2 is predominately hydrophobic in nature (lipophilic compound) C-ter TM1 TM4 • Mechanism of action may be to restrict the TM2 inter-helical conformational rearrangement Helix8 required for receptor activation ICL1 ICL2

Source: Cheng et al., Nature, 2017; Brown et al., SLAS Discovery, 2018

22 PAR2 PeptiDream Collaboration

• PeptiDream DELT focuses on peptide display

• Very successful hit generation approach for wide array of targets

• Utilising the PAR2 StaR in collaboration with Heptares Peptidream have identified several series of potent cyclic peptide antagonists of PAR2

• Current efforts seek to improve potency and stability of these very encouraging peptide lead compounds using SBDD

PAR2 X-ray complex with peptide ligand

23 3

GPCRs and Immuno-Oncology

24 GPCRs and Immunology Multiple GPCR families are commonly associated with the immune system

CHEMOKINE

NEUROKININ

ADENOSINE COMPLEMENT

FORMYL PEPTIDE CANNABINOID

LYSOPHOPHOLIPID (S1P)

HISTAMINE PARS

pH-SENSING EICOSINOID

25 The Immune Response to Cancer Antigen Presentation – T-cell Trafficking/Activation – Tumor Microenvironment

• Many human cancers exploit inhibitory “immune checkpoint pathways” to evade the anti-tumor immune response. • Immuno-oncology approaches seek to: • Boost the presentation of cancer antigens to the immune system, • Prime and activate the effector arm of the immune response, • Augment migration of immune cells in to tumors • Reduce activity of suppressor mechanisms

• High concentrations of adenosine in the tumor Treg microenvironment is a key immune inhibitory TAN Tumor mechanism in many cancers MDSC Microenvironment eT-cell ↓ immune cell suppression TAM ↑ eff T-cells

Adapted from Immunity 2013 39, 1-10DOI: (10.1016/j.immuni.2013.07.012

26 Discovery of A2A Receptor Antagonist - HTL1071/AZD4635 Impact of SBDD on A2A Hit ID → LO → DC

Preladenant Hit 1 Hit 2 HTL1071 / AZD4635

O S O Virtual BPM & N SBDD N N N Screen further VS Cl N N N N NH2 N ‘core hop’ N NH2 N NH2 N F OH H2N N N N N N N A2A pKi 8.8 A2A pKi 8.5 A2A pKi 6.9 A2A pKi 8.8 O MW 503, clogP 2.4 MW 310, clogP 3.1 MW 248, clogP 2.7 MW 316, clogP 2.7 LE 0.32, LLE 6.4 LE 0.52, LLE 5.4 LE 0.50, LLE 4.2 LE 0.49, LLE 5.2 CNS MPO 3.3 CNS MPO 4.6 CNS MPO 5.2 CNS MPO 5.1

• Poor CNS physchem properties • Novel non-furan containing • Novel triazene template • Improved LLE • Furan containing • Mod. selectivity (vs A1) • No structural alerts • Improved selectivity • Low selectivity (vs A1) • Improved metabolic stability • Mod. metabolic selectivity

SBDD platform approach significantly impacted • High efficiency leads identified using ‘enhanced homology model’ directed virtual screening identification & design of highly differentiated A2a ligands • SBDD guided approach used to drive LLE & selectivity enhancements

Sources: Langmead et al. J. Med. Chem. 2012, 1904; Congreve et al. J. Med. Chem. 2012, 1898

27 AstraZeneca testing AZD4635 in Phase 1b/2 studies AZD4635 as monotherapy or in combination in tumors of high unmet need Partnered with: AZD4635 (A2aR)

ClinicalTrials.gov Identifier: NCT02740985 • I-O naïve and post immunotherapy tumors Monotherapy Primary

AZD4635 AZD4635 AZD4635 AZD4635 AZD4635 AZD4635 completion date (A2aR antagonist) Post IO NSCLC IO naïve mCRPC IO naïve CRC Other IO naïve Post IO other 2020

• I-O naïve and post immunotherapy tumors Combo with Primary durvalumab AZD4635 + Durvalumab AZD4635 + Durvalumab completion date (anti-PD-L1) Post IO NSCLC IO naïve mCRPC 2020

ClinicalTrials.gov Identifier: NCT03381274 • Locally advanced/metastatic NSCLC with EGFR mutation Combo with Primary oleclumab AZD4635 + Oleclumab completion date (anti-CD73) NSCLC with EGFRmut 2021

28 GPCRs as potential next-gen I/O therapies Multiple GPCRs and GPCR ligands are expressed in the tumor microenvironment

CCL2 A2b A2a C3a CXCL12 Mechanism A3 CCL5 A2a CXCR2 CCL17 A2a CXCR4 C3a CXCR5 Adenosine Antigen APC FMLP1 A2b CXCL1 FMLP1 Presentation A2a A3 CXCL5 C3a CXCL8 EP4 Mobilisation PGE2 A2b EP2 CX3CR1 CXCR4 CCR2 CXCR2 S1PR1 EP4 C5a C3 CCR8 C3a C5a EP2 Recruitment CCR1 EP4 CCR4 CXCR2 EP2 Neutrophil CXCR4 A2b CXCR1 CCR2 Activation

Suppression

ANTI TUMOR PRO TUMOR

29 Sosei Heptares AI Drug Discovery Platform Bioinformatics GPCR structure Computational Chemistry Cheminformatics

Pharmacology Biomolecular Structure AI driven: AI driven: AI driven: • Ligand design AI driven: • Target Selection • StaR design • Synthesis planning • ADMET prediction

Development Protein Engineering Medicinal Chemistry Translational Sciences

Data & descriptors

Machine Learning

Artificial Intelligence for Multi-Parametric GPCR Drug Discovery

30 Potential New GPCR Target Selection in I/O – Use of Bioinformatics GPCRs identified from transcriptomics analysis of T-reg cells from cancer patients

Findings from patient tissue analyses GPCRs/Ligands that are expressed differently

Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness Receptors of Tumor-infiltrating T Regulatory Cells P2Y14 (UDP-glucose) Immunity. 2016 Nov 15;45(5): 1135-1147. doi: 10.1016/j.immune.2016.10.021 ▲ ▲ CCR8 (CCL1/CCL8) • Transcriptomes of Treg cells infiltrating colorectal or non-small-cell lung cancers were compared to transcriptomes of the same subsets from normal ▲ CX3CR1 (CX3CL1/CCL26) tissues and validated at the single-cell level ▲ ETB receptor (Endothelin)

▲ GPR56 (orphan-adhesion)

• Preliminary data from bulk RNA-Seq analysis extracted and differentially ▼ GPR109B (3-hydroxyoctanoic acid)

expressed genes identified - 758 genes were listed as differentially ▼ GPR160 (orphan) expressed between TregC and TregH at the p=0.1 level Ligands

▲ (CCR1, CCR4 and CCR5) CCL3 • GPCRs/Ligands extracted from this list of differentially expressed genes ▲ (CCR8) CCL18 include: ▲ (CXCR5) CXCL13 A number of GPCR and GPCR ligands are differentially expressed tumor associated vs. non-tumor associated T-reg cells

• Gold denotes targets with existing Sosei Heptares StaR assets (stabilised receptors)

31 4

Summary

32 More than 10+ years of innovation at Sosei Heptares

 Validated and consolidated the use of X-ray crystallography and Cryo-EM for GPCR drug discovery StaR® Platform  At forefront of the field with multiple high impact publications Technology  Extensive development and use of biophysical methods for GPCRs, often for the first time

 Highly productive discovery engine with med chem phase of project generally less than 2 years  Average Hit to pre-PCC timeline of ~2 years across > 20 programs GPCR Drug Discovery  Identified / contributed to 22 Pre-Clinical Candidates in 10 years  Therapeutic mAb Discovery, although has been challenging, now established with PCC mAbs identified in partnerships

 Fully established Development Teams in the UK and Japan GPCR  Multiple clinical and non-clinical programs underway, with 8 clinical programs ongoing Drug Development  Proven development capability in Japan, having taken two drugs to market in Japan

33 Our partnered pipeline has advanced across multiple programs

Product/Program Modality1 Indication Partner Discovery Preclinical Phase 1 Phase 2 Phase 3 Marketed Japan Marketed Products (Out-licensed to Marketing / Distribution / Commercialization Partners) NorLevo® SME Emergency contraception ORAVI® SME Oropharyngeal candidiasis Partnered Pipeline - Respiratory Products (Traditional out-licensing) Seebri®/Ultibro® SME COPD QVM149 SME Asthma Partnered GPCR Pipeline (Traditional out-licensing/collaboration projects) A2a antagonist SME Multiple solid tumors A2a antagonist SME EGFRm NSCLC

M1 agonist SME Alzheimer’s disease

M4 agonist SME Alzheimer’s disease

M1/M4 dual agonist SME Alzheimer’s disease Single target SME Pain Multiple targets SME Multiple indications Multiple targets mAb Inflammation Partnered GPCR Pipeline (Co-development/profit share) CXCR4 mAb mAb Immuno-oncology Single target mAb Immuno-oncology Single target Peptide Inflammation Asset-centric Companies Orexin agonists SME Narcolepsy Orexin agonists SME Narcolepsy

1 Note: SME = small molecule; mAb = monoclonal antibody : Current stage : Next 12–18 months progress 34 Our proprietary pipeline now has 3 programs in clinical development

Product/Program Modality1 Indication Originator Discovery Preclinical Phase 1 Phase 2 Phase 3 Marketed

Proprietary GPCR Pipeline (Go-to-market/commercialize)

M1 agonist SME DLB (Japan)

mGlu5 NAM SME Neurology

SSTR agonist Peptide Endocrine disorders

CGRP antagonist SME Migraine

GLP-1 antagonist Peptide Metabolic diseases

GLP-2 agonist Peptide Intestinal failure

Orexin-1 antagonist SME Cocaine-use disorders

Apelin agonist Peptide PAH

GPR35 agonist SME Inflammatory bowel disorders

EP4 agonist SME Inflammatory bowel disorders

H4 antagonist SME Atopic dermatitis

PAR2 mAb mAb Atopic dermatitis

: Current stage Multiple candidates entering clinical development and next wave of targets in advanced discussions : Next 12–18 months progress

1 Note: SME = small molecule; mAb = monoclonal antibody

35 Thank you for your attention

SOSEI HEPTARES

PMO Hanzomon 11F The Steinmetz Building North West House 2-1 Kojimachi, Chiyoda-ku Granta Park, Cambridge 119 Marylebone Road Tokyo 102-0083 CB21 6DG London NW1 5PU Japan United Kingdom United Kingdom