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- Title
Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors.
- Authors
Gray, N S; Wodicka, L; Thunnissen, A M; Norman, T C; Kwon, S; Espinoza, F H; Morgan, D O; Barnes, G; LeClerc, S; Meijer, L; Kim, S H; Lockhart, D J; Schultz, P G
- Abstract
Selective protein kinase inhibitors were developed on the basis of the unexpected binding mode of 2,6,9-trisubstituted purines to the adenosine triphosphate-binding site of the human cyclin-dependent kinase 2 (CDK2). By iterating chemical library synthesis and biological screening, potent inhibitors of the human CDK2-cyclin A kinase complex and of Saccharomyces cerevisiae Cdc28p were identified. The structural basis for the binding affinity and selectivity was determined by analysis of a three-dimensional crystal structure of a CDK2-inhibitor complex. The cellular effects of these compounds were characterized in mammalian cells and yeast. In the latter case the effects were characterized on a genome-wide scale by monitoring changes in messenger RNA levels in treated cells with high-density oligonucleotide probe arrays. Purine libraries could provide useful tools for analyzing a variety of signaling and regulatory pathways and may lead to the development of new therapeutics.
- Publication
Science (New York, N.Y.), 1998, Vol 281, Issue 5376, p533
- ISSN
0036-8075
- Publication type
Journal Article
- DOI
10.1126/science.281.5376.533