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DRUG DISCOVERY
• Random Search
e.g., buying paintbrush, mop, hammer, gluestick, nail, etc. etc.
for hanging a picture frame on the wall
•
Rational Design
e.g., buying a nail for hanging the frame
•
Combinatorial Search
e.g., buying a box of nails of different sizes for hanging the frame
1
WHY COMBINATORIAL CHEMISTRY?
> 15 years
~ 1 NDA
> $500 million
~ 5 IND
Time
Cost
~ 250 in vivo
~ 500 in vitro
> 10,000 compounds
2
FULL TOOLBOX REQUIRED TO COMPETE
Biological
Discovery
Biodisposition
High Volume
Screening
Toxicity
IND
Lead Series
Combinatorial
Diversity
Efficacy
Structure, Design,
Informatics
Pharmacokinetics
Lead Discovery
Research
Iterative
Process
Preclinical
R&D
3
GENERATING A COMBINATORIAL LIBRARY
 MIXTURE SYNTHESIS
X
X
X
+
Y
Y
Y
……….. 9 products
4
 SPATIALLY ADDRESSABLE SYNTHESIS
I)
X
+
Y
II)
X
+
Y
III)
X
+
Y
Ser
Ala
Tyr
Arg
5
 SPLIT AND MIX STRATEGY
Y
SPLIT
Y
Y
Y
X
X
X
MIX
6
 SPLIT AND MIX STRATEGY
MIX and SPLIT
7
 DECONVOLUTION BY TAGGING
Y
SPLIT
Y
Y
Y
X
X
X
MIX
8
 DECONVOLUTION BY TAGGING (continued)
MIX and SPLIT
9
 DECONVOLUTION BY ENCODED DNA
SPLIT
N2
N1
N3
A2
A1
A3
MIX and SPLIT
A2
N1N2
N2N2
A1A2
N3N2
A2A2
A1
A3
N1N1
A3A2
N1N3
A1A1
N2N3
A1A3
N2N1
N3N1
A2A1
A3A1
N3N3
A2A3
A3A3
10