Lipinski-Arrowhead-2012-drug-repositioning.ppt

drug repurposing

1. Drug repositioning: out of the box
opportunities despite data and
chemistry challenges
Christopher A. Lipinski
[email protected]
1Lipinski Arrowhead SFO 2012

2. 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.
Lipinski Arrowhead SFO 2012 2

3. Target-based drug discovery:
E1
E5
R2
R3
R4
R5
R6
R1
E2
E3 E4 E7
E6
DP 1 DP 2
D1
D2
3Lipinski Arrowhead SFO 2012

4. ….the real picture
R8
DP 5
E10
E9
E8
E1
E5
R2
R3
R4
R5
R6
R1
E2
E3 E4 E7
E6
DP 1 DP 2
R7
R9
R10
R11
R12
DP 3
DP 4
E7
E8
D1
D2
4Lipinski Arrowhead SFO 2012

5. Has drug discovery gone wrong?
•Prevailing mantra: identify a mechanism and
discover a selective ligand for a single target
•Counter responses:
•Improve target validation, academic collaboration
•Spread financial risk – collaborations, outsourcing
•Phenotypic screening
•Drug repurposing
•Multi targeted drug discovery
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6. Phenotypic screening advantage
The majority of small-
molecule first-in-class NMEs
that were discovered
between 1999 and 2008 were
first discovered using
phenotypic assays (FIG.
 2): 28
of the first-in-class NMEs
came from phenotypic
screening approaches,
compared with 17 from
target-based approaches.
How were new medicines
discovered? David C.
 Swinney
and Jason Anthony Nature
Reviews Drug Discovery 2011
(10) 507-519.
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7. Drugs Under Active Development involved in Multiple Programs
Source: Thomson Reuters Integrity℠
Within Integrity there are
over 20,000 active preclinical
drug programs.
Here we have taken a sample
set of 1000 active preclinical
drug programs.
Note – this includes all those with anything active in 10
or over programs, hence the apparent increase.
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Lipinski Arrowhead SFO 2012

8. Phenotypic observations
•30% of 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
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9. Unbiased Phenotypic Screening
•“Phenotypic Screening” as often used
–Any route to discovery other than “hypothesis-
based” discovery
•e.g. Serendipitous finding in the clinic, focused screen in
a single model
•Systematic Unbiased Phenotypic Screen
•Melior’s approach involving comprehensive evaluation
in a spectrum of animal models independent of
candidates mechanism or primary therapeutic area
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10. Repurposed diabetes drug
10
Lyn kinase activator
new mechanism,one of 264
mechanism possibilities
Lipinski Arrowhead SFO 2012

11. Source: Thomson Reuters Integrity℠
The Key Therapeutic Areas by no. of Associated Targets
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12. Conclusions
•Drug repurposing is independent of drug
discovery method
•Phenotypic screens cast a broad net
•Reductionist / mechanistic approach
unnecessarily limits opportunities
–eg. current NCATS repositioning
•Chemistry structural information required
for most computational approaches
–eg. current NCATS missing structures
12Lipinski Arrowhead SFO 2012