1 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

2 ~ 5 IND ~ 250 in vivo ~ 500 in vitro > 10,000 compounds > 15 years ~ 1 NDA > $500 million Time Cost WHY COMBINATORIAL CHEMISTRY?

3 Biological Discovery High Volume Screening Combinatorial Diversity Structure, Design, Informatics Lead Series Biodisposition Toxicity Efficacy Pharmacokinetics IND Lead Discovery Iterative Preclinical Research Process R&D FULL TOOLBOX REQUIRED TO COMPETE

4 GENERATING A COMBINATORIAL LIBRARY XXXYYY + ……….. 9 products  MIXTURE SYNTHESIS

5 Ser Ala Tyr Arg  SPATIALLY ADDRESSABLE SYNTHESIS XY + I) XY + II) X Y + III)

6  SPLIT AND MIX STRATEGY X XX Y Y YY MIX SPLIT

7  SPLIT AND MIX STRATEGY MIX and SPLIT

8  DECONVOLUTION BY TAGGING Y Y YY X XX MIX SPLIT

9  DECONVOLUTION BY TAGGING (continued) MIX and SPLIT

10  DECONVOLUTION BY ENCODED DNA MIX and SPLIT SPLIT A1 N1 A2 N2 A3 N3 A2A2 A1A2 N1N2N2N2 A3A2 N3N2 A2A1 A1A1 N1N1N2N1 A3A1 N3N1 A2A3 A1A3 N1N3N2N3 A3A3 N3N3 A2 A3 A1