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.

1. Best Strategies to Undertake a
Drug Repurposing Initiative
1 © 2009 PerkinElmer

2. 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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3. 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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4. Phenotypic vs Target Based R&D
How were new medicines discovered?
David C. Swinneyand Jason Anthony
Nature Reviews - Drug Discovery, vol.10 p507 2011
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5. Phenotypic vs Target Based R&D
How were new medicines discovered?
David C. Swinneyand Jason Anthony
Nature Reviews - Drug Discovery, vol.10 p507 2011
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6. Phenotypic vs Target Based R&D
19/20th century 20/21st century
(serendipity, RDD) (technology, industrialization)
then!
now what?
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7. Drug Discovery Processes
Traditional:“target-driven”
Target
ID & Val
Reverse Pharmacology: “Phenotypic”
Lead
Drug
Discovery
Lead In cellulo/vitro
Optimization In vivo testing
testing
Candidate Mechanistic
Development Study
Drug
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8. Phenotypic vs Target Based R&D
Target Based Phenotypic
• Compatible with both small • Compatible with both small molecules
molecules and biologics and biologics
• Controlled environment • Complex environment
 Simplistic / “one-dimensional”  “Black-box”/ multifactorial
 avoid off-target artifacts  In-vivo / In vitro platforms
 robustness and reproducibility  Multiple targets & interactions
• Molecular mechanism of action • Molecular mechanism of action
 Pharmacodynamics studies  Pharmacokinetics / ADMET
(Kd, Ki, etc) functional studies
• Well suited for: • Well suited for:
 Intractable targets (eg. lipid  Drug repositioning / repurposing
kinases)
 Fragment-based screening
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9. “Target-based Shotgun” characterization: in vitro/cellulo molecular signature
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10. In cellulo / vivo molecule signatures
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11. Reconciling phenotypic and target-driven observations
30% o f 400 compounds profiled show new beneficial biology
Up to 90% of new indications are driven by “on-target” activities
Biology is complex and there is a tremendous amount that is not understood
Phenotypic 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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12. Success stories: Melior Pharmaceuticals (CRO)
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13. Success stories: Lilly / USC Partnership
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