-
Rob Cooke, SVP Biomolecular Structure
Application of structure-based drug discovery to G
protein-coupled receptors
NON-CONFIDENTIAL
May 2019 | © Heptares Therapeutics Limited
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2
The material that follows is a presentation of general
background information about Sosei Group Corporation and its
subsidiaries (collectively, the “Company”) as of the date of this
presentation. This material has been prepared solely for
informational purposes and is not to be construed as a solicitation
or an offer to buy or sell any securities and should not be treated
as giving investment advice to recipients. It is not targeted to
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offering of them and should not be considered as a recommendation
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securities.
The information contained herein is in summary form and does not
purport to be complete. Certain information has been obtained from
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implied, by the Company is made as to the accuracy, fairness, or
completeness of the information presented herein and no reliance
should be placed on the accuracy, fairness, or completeness of such
information. The Company takes no responsibility or liability to
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alter, modify or otherwise change in any manner the contents of
this presentation, in its own discretion without the obligation to
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This presentation contains “forward-looking statements,” as that
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achievements to differ materially from those in the forward looking
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that the expectations and assumptions reflected in the
forward-looking statements are reasonably based on information
currently available to the Company's management, certain forward
looking statements are based upon assumptions of future events
which may not prove to be accurate. The forward looking statements
in this document speak only as at the date of this presentation and
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non-GAAP financial measures contained in this presentation are not
measures of financial performance calculated in accordance with
IFRS and should not be considered as replacements or alternatives
profit, or operating profit, as an indicator of operating
performance or as replacements or alternatives to cash flow
provided by operating activities or as a measure of liquidity (in
each case, as determined in accordance with IFRS). Non-GAAP
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References to "FY" in this presentation for periods prior to 1
January 2018 are to the 12-month periods commencing in each case on
April 1 of the year indicated and ending on March 31 of the
following year, and the 9 month period from April 1 2017 to
December 31 2017. From January 1 2018 the Company changed its
fiscal year to the 12-month period commencing in each case on
January 1. References to "FY" in this presentation should be
construed accordingly.
Disclaimer
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Agenda
Introduction to GPCRs1
GPCR Platform and Discovery Examples2
GPCRs and Immuno-Oncology3
Summary4
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Introduction to GPCRs
1
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• 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
G Protein-Coupled Receptors (GPCRs) Super Family
Many Top-Selling Drugs Hit GPCRs ~ 30% of ALL prescription
drugs
http://oxycontinrems.com/default.aspxhttp://singulair.com/http://dc118.4shared.com/img/NeebcUJE/s7/seroquel_logo.jpghttp://www.benicar.com/index.htmlhttp://www.ventolin.com/index.htmlhttp://www.byettahcp.com/Pages/index.aspxhttp://www.planetdrugsdirect.com/Drugs/Detrol-LA/1980/
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GPCR Targets as a Source of Drugs
Source: Christopher et al. Med. Chem. Rev. 2018, 69
FIC vs BIC GPCR ApprovalsFDA Drug Approvals
• 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)
25%
22%12%
10%
5%4%4%3%3%7%
5%
FIC PK Selectivity PolypharmacyCombination Toxicology CNS
penetration Phys ChemReceptor kinetics Route Potency
28
53
39
3035
27 2417
21
36
20 22 1824 26 21
30
39
27
4145
311
3 5 2 47 5 4 4 5 4 5
114 5 3 6 3
814
0
10
20
30
40
50
60
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
Total GPCR
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GPCR Platform and Discovery Examples
2
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Key to our Structure-Based Drug Discovery (SBDD)The Stabilised
Receptor (StaR®)
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10
30
50
70
-10 10 30 50 70
Drug Candidates
StaRUnstableNativeGPCR
FragmentScreening
X-rayCrystallography
Receptor Kinetics
• 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
Chart1
Chart2
41.914.7645.82-33.054.971.51
41.233.4615.47-27.975.033.1
39.71.5938.53-5.625.192.67
40.582.4529.71-4.595.257.61
40.183.1227.4-4.45.25-2.57
40.713.61-4.015.420.78
41.993.2-45.526.73
45.825.03-3.935.6112.58
15.47-3.835.63-1.52
38.53-3.745.750.76
29.71-3.735.78-3.46
27.4-3.736.08-3.03
-3.76.15-2.6
-3.496.28-2.22
-3.36.56-1.96
-3.256.73-1.87
-3.196.79-1.49
-3.026.92-1.02
-3.016.99-0.84
-37.66-0.8
-2.997.760.41
-2.987.780.63
-2.917.880.67
-2.848.120.79
-2.848.191.1
-2.828.48
-2.788.61.67
-2.779.43
-2.729.61.9
-2.639.963.48
-2.599.994.89
-2.5210.195.1
-2.4610.35
-2.4610.35
-2.4510.46
-2.4210.795.67
-2.4210.811.51
-2.3810.8214.06
-2.3411.25
-2.313.18
-2.2913.42
-2.2513.58
-2.2514.28
-2.2116.34
-2.216.53
-2.1917.52
-2.1920
-2.1520.24
-2.1520.32
-2.1421.24
-2.1221.86
-2.1223.27
-2.0823.63
-2.0727.13
-2.0628.77
-2.0233.4
-2.0133.88
-1.9746.78
-1.8853.5
-1.8757.91
-1.7860.52
-1.755.22
-1.755.41
-1.745.53
-1.681.83
-1.621.26
-1.613.57
-1.593.64
-1.593.95
-1.564
-1.514.07
-1.494.44
-1.484.52
-1.454.53
-1.454.66
-1.444.76
-1.444.79
-1.432.52
-1.423.32
-1.413.42
-1.412.26
-1.352.28
-1.34
-1.33
-1.32
-1.3
-1.3
-1.28
-1.24
-1.21
-1.2
-1.18
-1.15
-1.12
-1.12
-1.11
-1.11
-1.08
-1.08
-1.06
-1.06
-1.03
-0.98
-0.98
-0.96
-0.95
-0.95
-0.94
-0.92
-0.92
-0.92
-0.88
-0.88
-0.82
-0.81
-0.77
-0.76
-0.75
-0.73
-0.7
-0.66
-0.65
-0.65
-0.64
-0.64
-0.62
-0.6
-0.54
-0.51
-0.51
-0.48
-0.47
-0.47
-0.47
-0.45
-0.45
-0.41
-0.41
-0.41
-0.4
-0.4
-0.38
-0.38
-0.38
-0.36
-0.35
-0.33
-0.32
-0.32
-0.3
-0.28
-0.28
-0.27
-0.26
-0.25
-0.25
-0.24
-0.21
-0.2
-0.17
-0.17
-0.15
-0.12
-0.11
-0.07
0.08
0.09
0.11
0.12
0.13
0.16
0.17
0.18
0.21
0.21
0.24
0.24
0.34
0.42
0.43
0.47
0.67
0.67
0.79
0.8
0.85
0.88
0.89
0.92
0.94
1
1.15
1.17
1.21
1.3
1.4
1.42
1.44
1.45
1.46
1.68
1.69
1.72
1.77
1.81
1.84
1.99
2.17
2.18
2.19
2.21
2.26
2.26
2.54
2.61
2.68
2.97
3.05
3.13
3.31
3.34
3.35
3.63
4.31
4.58
4.77
2.22
36.29
15.6
-14.33
5.1
48.59
1.51
38.49
2.85
-12.79
1.76
46.12
1.79
36.99
9.37
-3.03
1.77
32.79
1.8
37.64
0.9
-2.82
1.22
32.89
2.38
37.04
-0.84
-1.25
7.87
37.24
1.79
37.88
-3.19
8.27
26.65
2.63
36.98
-2.37
3.64
74.63
38.75
-2.24
8.63
37.83
-2.36
7.2
27.73
-3.25
9.87
64.41
-2.66
7.42
13.4
-0.8
11.74
9.36
0.83
3.76
37.2
-2.06
7.82
14.43
-2.54
8.46
7.04
-2.81
5.49
16.16
-1.59
9.65
10.3
-2.27
7.59
18.26
-2.29
4.02
12.58
0.5
7.92
7.54
-1.64
12.26
6.37
-3.28
7.28
6.93
-1.29
7.11
15.43
-2.97
12.32
8.44
-2.69
9.85
7.22
-1.4
7.74
-2.29
7.29
10.06
-2.39
6.79
2.97
12.82
7.22
-1.55
17.03
24.92
-2.77
8.5
15.49
0.34
13.52
18.98
-1.15
18.12
1.11
8.91
-0.74
10.33
-1.29
6.81
22.66
-1.97
17.68
25.21
-1.24
14.82
30.7
-1.83
15.47
-0.32
14.93
-1.75
11.27
-1.54
18.34
-1.06
21.79
1.65
20.91
-1.3
17.38
-2.03
24.97
-0.06
25.16
1.65
21.27
-2.93
26.4
0.62
31.36
-1.06
30.93
-1.98
28.9
2.37
19.18
-1.01
27.92
-2.25
38.34
0.21
37.26
-1.31
43.04
-1.92
58.73
-1.26
70.65
-1.87
73.47
-1.25
51.22
-1.33
11.62
-1.42
13.04
-0.67
11.62
-0.7
5.54
-1.89
5.38
2.38
5.11
-1.05
5.36
0.24
5.33
-1.7
9.21
-2.36
6.31
-0.47
5.41
-2.06
6.37
3.15
7.83
-1.8
5.4
-1.82
6.72
-1.44
8.72
-2.26
5.25
-0.63
5.88
-1.94
6.94
1.96
6.12
0.17
6.92
-1.58
-18.87
3.94
-0.75
-1.46
3.04
0.4
-0.73
-1.51
-0.55
3.33
-2.48
-1.9
-0.43
-0.77
-1.26
0.42
-1.67
-1.76
-0.67
-2.07
-2.12
-0.59
-0.03
0.09
-0.56
-0.79
-0.22
0.05
-1.61
-1.58
4.43
-1.04
-0.63
-0.97
-0.34
-1.05
1.78
0.57
-1.84
-0.61
-0.55
0.52
-1.04
0.16
1.41
-1.53
-0.74
-1.56
1.27
2.77
0.93
-0.02
-1.5
1.41
-0.42
1.36
-0.32
-0.96
1.04
0.2
-0.09
-1.37
-0.15
0.01
1.13
0.04
-1.2
2.06
2.38
-0.5
3.55
2.22
0.7
-1.43
0.69
-0.2
0.54
-1.09
4.03
-0.13
-0.13
1.29
2.77
0.2
1.58
2.74
0.46
4.17
1.62
-0.19
-0.55
-0.6
1.18
0.7
1.33
0.14
2.95
2.11
0.91
0.18
2.66
0.56
1.49
-0.35
3.13
0
1.87
0.04
0.49
4.86
0
2.18
2.1
2.06
2.12
3.4
3.9
0.12
2.84
0.52
2.39
2.44
0.66
2.32
4.31
3.36
2.93
4.81
1.88
4.67
3.17
3.1
4.16
2.27
4.43
3.49
1.3
4.31
4.56
4.78
4.95
3.18
4.24
A2a pts
AnalyteA2aB1spec A2a hitsspec b1 hitsvery weak/nonbinders (
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Step-wise Receptor EngineeringSosei Heptares Unique
Stabilisation Platform
• 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
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StaR® Technology Reliably Delivers X-ray Structures
SEC
Express Membrane Solubilise Purify SEC LCP/VD Setup Crystals
Optimise StructureUnstableNativeGPCR
StaR
Screening: Fusions Positions Ligands Detergents
Semi-automated scout purification of multiple
constructs/conditionsMilligram quantities of up to 6 proteins in 24
hours
Crystals grown in lipidic cubic phase
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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
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• For many years cryo-EM images of proteins were limited to
approx7Å
• 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
(glutamate dehydrogenase, 334kDa) and for a 64kDa particle
(hemoglobin, 3.2Å resolution)
Now Applying Cryo-EM to GPCRs
Richard Henderson Joachim Frank Jacques Dubochet“for developing
cryo-electron microscopy for the high-resolution
structure determination of biomolecules in solution”
Nobel Prize in Chemistry (2017) Current Opinion in Structural
Biology, Volume 41, 2016, 194–202
Cryo-EM structure of the activated GLP-1 receptor in complex
with G proteinZhang et al., Nature, 2017
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• 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
• 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)
X-ray Diffraction remains a Key Structural Engine
CRF1 mGlu5GCGR
CCR9 PAR2 GLP1R C5aR
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Ligand-independent thermostabilisationHit Generation: Novel
Assay Screening Platforms
• 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
-
Caffeine
β1Control
A2AControl
β1 Hits
A2A Hits
A2A
β 1AR
Typical results for ‘well behaved’ hits
• SPR screening with A2A as counter screen
• Several related hits
Hit Generation: SPR Fragment Screening Platform
Ki = 68 nMLE = 0.65
N
NH
NH
N
N
NH
Ki = 224 nMLE = 0.53
KD = 16 µMLE = 0.41
N
NH
F
FF
Source: Christopher et al. J. Med. Chem. 2013, 56, 3446
KD = 16 µMLE = 0.41
N
NH
F
FF
15
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Establishing invitro assays to support primary hit
identificationHit Generation: In Vitro Pharmacology
Building platforms to support hit ID on a target by target
basis
Inhibition n=1
Inhi
bitio
n n=
1
Library hit ID visualisations Visualisation tools integrated to
enable hit identification and selections for follow-up
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
Structure-sequence analysis and mutation study designCADD:
Virtual screening and ligand design methods
1. Generation of high throughput in vitro assays to 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
• Generation of frozen cells expressing target where possible to
support consistency and flexibility
• Large scale membrane preparations generated for competition
binding studies
• Maximise hit identification through use of stabilised proteins
to build unique invitro assay platforms in parallel with SPR
biophysics group (see next slide)
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17
Working with Chemistry and Pharmacology to identify hits and
design novel ligandsVirtual Screening and Computer-Aided Drug
Design Approaches
Docking and Structural protein-ligand Interaction Fingerprint
scoring
In-house MedChem Ideas algorithm for library
designGRID/WaterFLAP/waterMAP GPCR binding site analysis
aMetaD – Solvation Factor FEP+ cycle
Shape/pharmacophore screenings
LiveDesign
Development and application of VS and CADD methods
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• 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)
• LiveDesign + 3D brainstorm sessions (Vida) for data
integration, analysis, and 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.
-
mGlu5 pKi 5.2clogP 1.1
LE 0.40, LLE 4.1
NN
NN
NN
mGlu5 pKi 9.3clogP 2.6
LE 0.60, LLE 6.7
NN
NN
Cl CN
FN O
O
H HOH
mavoglurantmGlu5 pKi 8.0
clogP 3.1LE 0.47, LLE 4.9CNS MPO 5.2
HTL14242mGlu5 pKi 9.3
clogP 3.0LE 0.57, LLE 6.3CNS MPO 5.5
N
N
Cl CN
N
F
Acetylene containing Poor PK (rat F 22%)
Novel non-acetylene containing chemotypeSub optimal potency
& LLE
Significant LLE & LE enhancements
Sub optimal metabolic stability
Good PK (F%>80% - 2 species)
High RO (ED50 0.3 mg/Kg)
Clean off-target profile
Fragment Screen
Advanced homology modelling
X-ray driven SBDD
18
Lead Optimisation Example: mGlu5 Receptor NAM
Source: Christopher et al. J. Med. Chem. 2015, 58, 6653
HTL0014242 Phase 1 clinical study 2019 - Double blind placebo
controlled single ascending dose in healthy volunteers
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19
Amyotrophic Lateral Sclerosis Glutamate & mGlu5 in ALS
mGlu5 expression in ALS spinal cord glia correlated with markers
of glial activation (GFAP)
Readouts Vehicle HTL001424225D CohortHTL001424275D cohort
Riluzole
Effect on onset of clinical signs of disease ✕ ✕ - -
Increased number of motor neurons at 90D ✕ ✕ ✓ -
Reduction in GFAP staining at 90 days in SC ✕ ✓ ✓ ✕
Reduction in Iba1 staining at 90 days in SC ✕ ✓ ✓ ✕
Improvement in motor function as seen on rotarod ✕ ✕ ✓ -
Effect on survival ✕ ✕ ✕ -
Summary of mGlu5 effects in the SOD1G93A model
Source: Shaw P., BMJ vol 318; 1999; Bonficino et al.,
Neuropharmacology vol 123; 2017
• Glutamate-mediated toxicity is recognised as a mechanism of
neuronal injury
• Glial cells reduced capacity to uptake glutamate
• Increased glutamate receptor expression post-synaptically
• Also evidence of neuroinflammation – activation of glial cells
(astrocytes and microglia)
• Partial knockdown of mGlu5 receptor increases motor
performance and survival in mouse models (Bonficino et al.,
2017)
-
Finding new Allosteric Binding Sites using StaRs
Hollenstein et al. Nature (2013)
CRF1Receptor
Oswald et al., Nature (2016)
C-C chemokine Receptor type 9
Cheng et al., Nature (2017)
Protease-Activated Receptor 2
21
Family Aligands
TM7
TM5 TM6
Jazayeri et al., Nature (2016)
Glucagon Receptor
Extra-helical site
Deep allosteric site
Intracellular site
Intra-helical and extra-helical allosteric sites
20
-
C-ter
AZ8838
TM7 TM1
TM3
TM4
TM5
TM6
• Collaboration with AZ, fragment and HTS screening
• Antagonists inhibit peptide and protease activation of the
receptor
• Difficult to optimise in the absence of structural
understanding
• Binding site identified in PAR2 X-ray structure
• AZ8838 completely buried in a small binding pocket, lined by
residues from TM1-3, TM7, ECL2
Hit Generation Example: PAR2 Receptor Antagonist Discovery
ECL2
ECL1
ECL3
ICL1Helix8
ICL2
N-ter
TM7
TM1
TM2TM3TM4
TM5TM6
Cheng et al. Nature, 2017
21
F
OH
N
HN
AZ'8838
-
22
PAR2 in Complex with X-Chem Hit AZ3451Hit Generation using DELT
for PAR2
Source: Cheng et al., Nature, 2017; Brown et al., SLAS
Discovery, 2018
• X-Chem DNA encoded library technology
• Binding hits - confirmed as functional antagonists of PAR2
receptor
• AZ3451 binds in novel extra-helical site
• Interaction with PAR2 is predominately hydrophobic in nature
(lipophilic compound)
• Mechanism of action may be to restrict the inter-helical
conformational rearrangement required for receptor activation
ECL2
ECL1
ECL3
ICL1
Helix8
ICL2
N-ter
C-ter
TM7
TM1TM2
TM3
TM4
TM5TM6TM4
TM5
AZ3451TM7
TM1
TM2
TM3
TM6
N
NO
O
BrO
NH
N
AZ3451
-
23
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
-
24
GPCRs and Immuno-Oncology
3
-
25
Multiple GPCR families are commonly associated with the immune
systemGPCRs and Immunology
COMPLEMENT
FORMYL PEPTIDE
CHEMOKINE
ADENOSINE
NEUROKININ
HISTAMINE PARS
EICOSINOID
CANNABINOID
LYSOPHOPHOLIPID (S1P)
pH-SENSING
-
26
Antigen Presentation – T-cell Trafficking/Activation – Tumor
Microenvironment
• Many human cancers exploit inhibitory “immune checkpoint
pathways” to evade the anti-tumorimmune 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 tumormicroenvironment
is a key immune inhibitory mechanism in many cancers
The Immune Response to Cancer
Adapted from Immunity 2013 39, 1-10DOI:
(10.1016/j.immuni.2013.07.012
Tumor Microenvironment↓ immune cell suppression↑ eff T-cells
eT-cell
Treg
TANMDSC
TAM
-
27
Sources: Langmead et al. J. Med. Chem. 2012, 1904; Congreve et
al. J. Med. Chem. 2012, 1898
Discovery of A2A Receptor Antagonist - HTL1071/AZD4635 Impact of
SBDD on A2A Hit ID → LO → DC
Preladenant Hit 1 Hit 2 HTL1071 / AZD4635
A2A pKi 8.5MW 310, clogP 3.1
LE 0.52, LLE 5.4CNS MPO 4.6
A2A pKi 6.9MW 248, clogP 2.7
LE 0.50, LLE 4.2CNS MPO 5.2
A2A pKi 8.8MW 503, clogP 2.4
LE 0.32, LLE 6.4CNS MPO 3.3
Virtual Screen
BPM & further VS‘core hop’
SBDD
A2A pKi 8.8MW 316, clogP 2.7
LE 0.49, LLE 5.2 CNS MPO 5.1
NN
N
N
NH2
F
ClN
N
N
NH2
OH
S
NN
N NH2
O
O
N
N
NN
NN
N
H2N N
O
• Poor CNS physchem properties• Furan containing • Novel
non-furan containing• Mod. selectivity (vs A1) • Novel triazene
template• No structural alerts• Low selectivity (vs A1)• Mod.
metabolic selectivity
• Improved LLE• Improved selectivity• Improved metabolic
stability
• High efficiency leads identified using ‘enhanced homology
model’ directed virtual screening• SBDD guided approach used to
drive LLE & selectivity enhancements
SBDD platform approach significantly impacted identification
& design of highly differentiated A2a ligands
-
ClinicalTrials.gov Identifier: NCT02740985
ClinicalTrials.gov Identifier: NCT03381274
28
AZD4635 as monotherapy or in combination in tumors of high unmet
needAstraZeneca testing AZD4635 in Phase 1b/2 studies
Partnered with: AZD4635(A2aR)
MonotherapyAZD4635
(A2aR antagonist)
Primary completion date 2020
Combo with oleclumab(anti-CD73)
Primary completion date 2021
• I-O naïve and post immunotherapy tumors
Combo with durvalumab(anti-PD-L1)
Primary completion date 2020
• I-O naïve and post immunotherapy tumors
• Locally advanced/metastatic NSCLC with EGFR mutation
AZD4635Post IO NSCLC
AZD4635 IO naïve mCRPC
AZD4635IO naïve CRC
AZD4635Other IO naïve
AZD4635Post IO other
AZD4635 + DurvalumabPost IO NSCLC
AZD4635 + DurvalumabIO naïve mCRPC
AZD4635 + OleclumabNSCLC with EGFRmut
-
29
Multiple GPCRs and GPCR ligands are expressed in the tumor
microenvironmentGPCRs as potential next-gen I/O therapies
A2bA2a
C3a
APC
Neutrophil
A2aA3
A2a C3aCXCR2
CXCR4CXCR5
A2a A3FMLP1
CX3CR1
A2b
PGE2
CXCL1CXCL5CXCL8
Adenosine
CCL5CCL17
CCL2
C3
CXCL12
C5aA2b EP2CXCR2
C3a
FMLP1C3aEP4
C5aCXCR2
CXCR4CCR2
A2bEP2
EP4CCR1
CXCR1
CCR2CXCR4
EP2EP4
CCR4CCR8S1PR1
ANTI TUMOR PRO TUMOR
Mechanism
Antigen Presentation
Mobilisation
Recruitment
Activation
Suppression
-
30
Sosei Heptares AI Drug Discovery Platform
AI driven:• Ligand design
• Synthesis planning
Artificial Intelligence for Multi-Parametric GPCR Drug
Discovery
Machine Learning
Data & descriptors
GPCR structure Computational Chemistry Cheminformatics
AI driven:• ADMET prediction
Translational SciencesMedicinal ChemistryProtein Engineering
AI driven:• StaR design
Biomolecular Structure
AI driven:• Target Selection
Bioinformatics
Pharmacology
Development
-
31
GPCRs identified from transcriptomics analysis of T-reg cells
from cancer patients Potential New GPCR Target Selection in I/O –
Use of Bioinformatics
• Transcriptomes of Treg cells infiltrating colorectal or
non-small-cell lung
cancers were compared to transcriptomes of the same subsets from
normal
tissues and validated at the single-cell level
• Preliminary data from bulk RNA-Seq analysis extracted and
differentially
expressed genes identified - 758 genes were listed as
differentially
expressed between TregC and TregH at the p=0.1 level
• GPCRs/Ligands extracted from this list of differentially
expressed genes
include:
Findings from patient tissue analyses
Transcriptional Landscape of Human Tissue Lymphocytes Unveils
Uniqueness of Tumor-infiltrating T Regulatory CellsImmunity. 2016
Nov 15;45(5): 1135-1147. doi: 10.1016/j.immune.2016.10.021
A number of GPCR and GPCR ligands are differentially expressed
tumor associated vs. non-tumor associated T-reg cells
Receptors
▲ P2Y14 (UDP-glucose)
▲ CCR8 (CCL1/CCL8)
▲ CX3CR1 (CX3CL1/CCL26)
▲ ETB receptor (Endothelin)
▲ GPR56 (orphan-adhesion)
▼ GPR109B (3-hydroxyoctanoic acid)
▼ GPR160 (orphan)
Ligands
▲ (CCR1, CCR4 and CCR5) CCL3
▲ (CCR8) CCL18
▲ (CXCR5) CXCL13
GPCRs/Ligands that are expressed differently
• Gold denotes targets with existing Sosei Heptares StaR assets
(stabilised receptors)
-
32
Summary
4
-
33
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
At forefront of the field with multiple high impact
publications
Extensive development and use of biophysical methods for GPCRs,
often for the first time
StaR® Platform Technology
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
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
GPCR Drug Discovery
Fully established Development Teams in the UK and Japan
Multiple clinical and non-clinical programs underway, with 8
clinical programs ongoing
Proven development capability in Japan, having taken two drugs
to market in Japan
GPCR Drug Development
-
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 CompaniesOrexin agonists SME Narcolepsy
Orexin agonists SME Narcolepsy
34
Our partnered pipeline has advanced across multiple programs
1 Note: SME = small molecule; mAb = monoclonal antibody
: Next 12–18 months progress: Current stage
-
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
35
Our proprietary pipeline now has 3 programs in clinical
development
1 Note: SME = small molecule; mAb = monoclonal antibody
: Next 12–18 months progress: Current stageMultiple candidates
entering clinical development and next wave of targets in advanced
discussions
-
Thank you for your attention
SOSEI HEPTARES
PMO Hanzomon 11F
2-1 Kojimachi, Chiyoda-ku
Tokyo 102-0083
Japan
The Steinmetz Building
Granta Park, Cambridge
CB21 6DG
United Kingdom
North West House
119 Marylebone Road
London NW1 5PU
United Kingdom
Application of structure-based drug discovery to G
protein-coupled receptors Disclaimer Agenda 1G Protein-Coupled
Receptors (GPCRs) Super FamilyGPCR Targets as a Source of Drugs2The
Stabilised Receptor (StaR®)Sosei Heptares Unique Stabilisation
PlatformStaR® Technology Reliably Delivers X-ray Structures Slide
Number 11Now Applying Cryo-EM to GPCRsX-ray Diffraction remains a
Key Structural Engine Hit Generation: Novel Assay Screening
PlatformsSlide Number 15Hit Generation: In Vitro
PharmacologyVirtual Screening and Computer-Aided Drug Design
ApproachesLead Optimisation Example: mGlu5 Receptor NAMGlutamate
& mGlu5 in ALSSlide Number 20Slide Number 21Hit Generation
using DELT for PAR2Slide Number 233GPCRs and ImmunologyThe Immune
Response to CancerSlide Number 27AstraZeneca testing AZD4635 in
Phase 1b/2 studies GPCRs as potential next-gen I/O therapiesSosei
Heptares AI Drug Discovery PlatformPotential New GPCR Target
Selection in I/O – Use of Bioinformatics4More than 10+ years of
innovation at Sosei HeptaresOur partnered pipeline has advanced
across multiple programsOur proprietary pipeline now has 3 programs
in clinical developmentThank you for your attention
