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Can target-based drug discovery be reconciled with phenotypic assays in the context of drug repurposing? One of the questions discussed at the SLAS Drug Repurposing SIG meeting at SLAS2013.
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11 © 2009 PerkinElmer© 2009 PerkinElmer© 2009 PerkinElmer
Best Strategies to Undertake a Drug Repurposing Initiative
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Objectives
Can target-based drug discovery be reconciled with phenotypic assays in the context of drug repurposing?What are the best practices in assay design?How should compounds be tackled?
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Attrition rates by phase
The Productivity Crisis in Pharmaceutical R&D, Fabio Pammolli, Laura Magazzini and Massimo Riccaboni, Nature Reviews Drug Discovery 2011 (10) 428-438.
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How were new medicines discovered? David C. Swinney and Jason AnthonyNature Reviews - Drug Discovery, vol.10 p507 2011
Phenotypic vs Target Based R&D
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Phenotypic vs Target Based R&D
How were new medicines discovered? David C. Swinney and Jason AnthonyNature Reviews - Drug Discovery, vol.10 p507 2011
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19/20th century(serendipity, RDD)
20/21st century(technology, industrialization)
now what?
Phenotypic vs Target Based R&D
then!
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Drug Discovery Processes
TargetID & Val
LeadDiscovery
LeadOptimization
CandidateDevelopment
Drug
Drug
In cellulo/vitro testing
In vivo testing
MechanisticStudy
Traditional:“target-driven”
Reverse Pharmacology: “Phenotypic”
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Phenotypic vs Target Based R&D
Target Based• Compatible with both small
molecules and biologics• Controlled environment
Simplistic / “one-dimensional” avoid off-target artifacts robustness and reproducibility
• Molecular mechanism of action Pharmacodynamics studies
(Kd, Ki, etc)• Well suited for:
Intractable targets (eg. lipid kinases) Fragment-based screening
Phenotypic• Compatible with both small molecules
and biologics• Complex environment
“Black-box”/ multifactorial In-vivo / In vitro platforms Multiple targets & interactions
• Molecular mechanism of action Pharmacokinetics / ADMET
functional studies• Well suited for:
Drug repositioning / repurposing
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“Target-based Shotgun” characterization: in vitro/cellulo molecular signature
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In cellulo / vivo molecule signatures
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Reconciling phenotypic and target-driven observations
30% o f 400 compounds profiled show new beneficial biologyUp to 90% of new indications are driven by “on-target” activitiesBiology is complex and there is a tremendous amount that is not understoodPhenotypic screening provides an opportunity to identify new clinically relevant uses of existing molecules driven by action on known molecular targets
Lipinski - Arrowhead SFO 2012
side vs off target effects?
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Success stories: Melior Pharmaceuticals (CRO)
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Success stories: Lilly / USC Partnership
