Held Jointly with the
2004 SIAM Annual Meeting

Oregon Convention Center
Portland, Oregon

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Structure-guided Drug Discovery using Fragment-based Lead Identification/lead Optimization

Jeff Blaney (for Stephen K. Burley), Structural GenomiX, Inc.

Structural GenomiX, Inc. (SGX) has developed an integrated target-to-lead platform that combines high-throughput X-ray crystallography with a fragment-based approach to lead identification/optimization. The proprietary FAST™ (Fragments of Active Structures) process exploits crystallographic screening to detect, visualize, and identify small ligands (MW 150-200) that are bound to the target protein. Each member of the FAST™ fragment/scaffold library was designed to be amenable to rapid chemical elaboration at two or three points of chemical diversity using high-throughput organic synthesis. Initial lead optimization involves using our knowledge of the co-crystal structure of the target-fragment complex and advanced computational chemistry tools to guide synthesis of small focused linear (one-dimensional) libraries. These linearly elaborated fragments/scaffolds are then evaluated with in vitro biochemical and cellular assays and co-crystallography. Thereafter, optimal variations at each point of chemical diversity are combined to synthesize focused combinatorial (two- or three-dimensional) libraries that are again examined with assays and co-crystallography. (The theoretical chemical diversity of the fully elaborated FAST™ fragment/scaffold library exceeds 160 million compounds.) These focused combinatorial libraries typically contain multiple novel compounds of low molecular weight (<350) that bind the target protein at low nM IC50 and already display considerable selectivity. Thereafter, compound series are prioritized for further medicinal chemistry and compound development efforts using the results of in vitro and in vivo DMPK/PD and in vitro toxicology studies in concert with structural information. Successful applications of the FAST™ fragment-based lead discovery/optimization process will be presented for both protein kinases and proteases.


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