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MDC Connects: Target discovery at AstraZeneca
1. Target Discovery at AstraZeneca
Davide Gianni
Functional Genomics – Discovery Sciences – BioPharmaceuticals R&D
Astrazeneca – Cambridge UK
MDC Webinar Series: Target Identification April 2020
2. Presentation outline
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Why is Target Discovery important?
Target Discovery Platforms at AstraZeneca
Project example
Summary
3. Why is Target Discovery important?
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Implementation of 5R framework is improving success rates, 4% (2010) to 19% (2016)
Drugs projects are still failing as a result of lack of efficacy
Effective Target Discovery is a critical to further reduce attrition rate
The5RFramework
Reasons why drug fail
2005-2010 2012-2016
Reasons for project closures
4. What makes a good drug target?
Lessons learned from AZ pipeline
Target linkage to disease and availability of translatable models for target discovery and
prosecution are critical features associated with clinical efficacy
Integrated target discovery engine should focus on model translatability and genetic target
validation to identify, prioritise and validate novel targets to reduce the clinical attrition rate
5. Target Discovery Through Functional Genomics
AstraZeneca Strategy
AZ CRUK Functional
Genomics Centre
AZ Functional
Genomics Group
Internal Target Discovery
platform (CRISPRn, CRISPRa,
secretome and small molecule
screening)
Pooled CRISPR screening
facility with capacity to run
150 pooled genome wide
screens for Oncology
AZ/IGI Research
Collaboration
Partnership with Innovative
Genomics Institute to create
CRISPRi and CRISPRa libraries
and apply to DDR
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AstraZeneca / IGI Research Collaboration
AZ/IGI Research
Collaboration
Partnership with Innovative
Genomics Institute to create
CRISPR inhibition and CRISPR
activation libraries and apply to
DDR
Established 2016; renewed 2018
DNA Damage Response & drivers of resistance
• Determine resistance mechanisms to DDR medicines in relevant
genetic backgrounds
DNA Repair and Precise Genome Engineering
• Identify genes that influence the balance of gene editing outcomes
in therapeutically interesting cell models
Jennifer Doudna and Luke Gilbert
7. Joint AZ-CRUK Functional Genomics Centre
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Vision: A world-leading centre of expertise in genetic screens, cancer
models, CRISPR vector design and computational approaches to big
data, whose goal is identify novel targets and resistance
mechanisms to create new cancer medicines
New collaboration that launched in 2019
AZ CRUK Functional
Genomics Centre
Pooled CRISPR screening
facility with capacity to run
150 pooled genome wide
screens for Oncology
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Joint AZ-CRUK Functional Genomics Centre
Creating new cancer medicines together
• Driving discovery
through innovation in
functional genomic
screening
• Cutting edge target
identification and
validation tools
• Leaders in small
molecule drug discovery
• Expertise in
pharmacology and
screening
• Clinical trials
• Leading global cancer
charity
• Deep expertise in
cancer biology and
models
• Extensive network of
scientists and drug
discovery expertise
9. In silico, in vitro and in vivo target validation
Creation of disease relevant cellular models
Target Discovery through Functional Genomics
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N
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N
H
NH
O
F
F
F
O
NH
N
NH 2
Small Molecules
Genome wide
CRISPR platforms
Secretome protein
library (2K)
Screening and hit deconvolution
e.g. chemoproteomics, bioinformatics
Pathway
Elucidation
Target Discovery
Patient Selection
Stratification
Combination
Therapies
AZ Functional
Genomics Group
Internal Target Discovery
platform platform (CRISPRn,
CRISPRa, secretome and small
molecule screening)
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Genome Wide Arrayed CRISPR Platform
Method development
• Cas9 Dox inducible system
• Use pools rather than clones increases relevance of screens
ODIN expression cassette
Cas9 mRNA
+
• More transient delivery of mRNA Cas9 increase relevance of screens
• Balance between
biological relevance
and screenability
cmRNA
tracrRNA
WG arrayed
CRISPR library
(KO & activation)
Phenotypic
assay
Disease
relevant model
ObLiGaRe Zinc
fingers
Cell line
generation
High content
imaging
Multivariate &
deep learning
analysis
Biological
interpretation
and hit ranking
QuBi
Automated acoustic
CRISPR library
dispensing
CV8000
11. Target discovery using CRISPR libraries: Impact to AZ pipeline
Identification of factors modulating Androgen Receptor Stability
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Value to Pipeline: The identification of regulators of Androgen Receptor (AR) stability will provide novel targets for the
treatment of Castrate Resistant Prostate Cancer (CRPC).
Hypothesis: Targeting proteins involved in regulation of the stability of the AR will result in degradation of the AR
protein & will provide a novel therapeutic approach in patients who have become resistant to Androgen Deprivation
therapy (ADT).
Project description:
• Cell Models Generation and Characterization: multiple prostate cancer cell
lines inducibly expressing Cas9
• Primary Screening Assay: Endogenous AR expression/nuclear translocation/
proliferation & AR dependant gene (FKBP5)
• Perturbation modality: CRISPRn and CRISPRa arrayed library
• Specific requirements for route to Target nomination: selective mechanism
leading to degradation of AR
AR Signalling
Ubiquitin Proteasome Pathway
12. Identification of regulators of AR stability to identify novel targets
for CRPC
Screening across multiple PC cell lines
expressing clinically relevant AR
variants
Identification of known & novel
regulators
Epigenetic Modulators
E3 Ubiquitin Ligases
Co-regulators
Regulators of Transcription
Splicing Factors
Current status:
Confirmed and ranked hit list
undergoing target validation
ARproteinlevel
Well data across primary screen: positive controls (blue), negative controls (green) & library gRNAs (black)
RZ’>0.8
Non-Targeting Control Positive Control (targeting AR)
Cas9 Cas9
FKBP5 FKBP5
AR N-terminal AR N-terminalAR C-terminal Receptor C-terminal
Morphology Morphology NucleiNuclei
Hit
Hit
Hit
Strong opportunity to impact AZ portfolio
13. Summary
• Target Discovery platforms are critically important to reduce clinical attrition rate
• Genetic linkage to disease and model translatability are significant discriminators of
success in identification of right target
• AZ Target Discovery platforms focussed on combining cutting edge screening
technologies with development of translatable biological models
• Project example of functional genomics screen in performed in prostate cancer cell
lines expressing clinically relevant AR variants using highly validated genome-wide
CRISPRn and CRISPRa libraries delivers new target opportunities for AZ portfolio
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14. Acknowledgements
Sam Peel, Douglas Ross-Thriepland, Patrick O’Shea, Sinead Knight & AZ Functional Genomics group
Rick Davies and Lovisa Holmberg-Schiavone Secretome library and collaboration
Steve Rees: VP: Discovery Biology
Bev Isherwood, Martin Main and Lorenz Mayr: legacy
Emanuela Cuomo and Marcello Maresca – experts in precise genome editing
Adam Corrigan, Yinhai Wang: Image Analysis, Machine Learning
Maria Luisa Guerriero, Aurelie Bornot, Natasha Karp: Quantitative Biology
James Lynch, Paul Smith, Arpan Desai, Sven Gopel, Gavin O’Mahony, Dave Smith, Simon Dovedi and
Lorna Ewart, Disease and technology experts
Jenna Bradley and Giovanni Ciotta : Cell line generation and molecular biology support
Eddy Rosello, David Lorenz + Yokogawa & Wako teams
Luke Gilbert and Raphael Sharfmann: External collaborators
15. AstraZeneca
Collaboration and Opportunities
Contact Details:
Davide.Gianni@astrazeneca.com
Cambridge, UK – New R&D Centre and Global HeadquartersDiscover more at openinnovation.astrazeneca.com
Career Opportunities:
http://www.astrazeneca.com/careers
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17. Confidentiality Notice
This file is private and may contain confidential and proprietary information. If you have received this file in error, please notify us and remove
it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the
contents of this file is not permitted and may be unlawful. AstraZeneca PLC, 1 Francis Crick Avenue, Cambridge Biomedical Campus,
Cambridge, CB2 0AA, UK, T: +44(0)203 749 5000, www.astrazeneca.com
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Confidentiality Notice
This file is private and may contain confidential and proprietary information. If you have received this file in error, please notify us and remove
it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the
contents of this file is not permitted and may be unlawful. AstraZeneca PLC, 1 Francis Crick Avenue, Cambridge Biomedical Campus,
Cambridge, CB2 0AA, UK, T: +44(0)203 749 5000, www.astrazeneca.com
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