Exploiting Chemical Libraries, Structure, and Genomics in the Search for Kinase Inhibitors

• DOI: 10.1126/science.281.5376.533
• Publication Date: 2002-07-27T09:37:56Z
• Authors: Nathanael S. Gray; Lisa Wodicka; Andy-Mark W. H. T...; Thea C. Norman; Soojin Kwon; F. Hernan Espinoza; David O. Morgan; Georjana Barnes; Sophie LeClerc; Laurent Meijer; Sung-Hou Kim; David J. Lockhart; Peter G. Schultz
• Keywords: Cyclin-dependent kinase complex; Structural genomics; Chemical library; Cyclin-dependent kinase 7

Selective protein kinase inhibitors were developed on the basis of unexpected binding mode 2,6,9-trisubstituted purines to adenosine triphosphate–binding site human cyclin-dependent 2 (CDK2). By iterating chemical library synthesis and biological screening, potent CDK2–cyclin A complex Saccharomyces cerevisiae Cdc28p identified. The structural for affinity selectivity was determined by analysis a three-dimensional crystal structure CDK2-inhibitor complex. cellular effects these compounds characterized in mammalian cells yeast. In latter case genome-wide scale monitoring changes messenger RNA levels treated with high-density oligonucleotide probe arrays. Purine libraries could provide useful tools analyzing variety signaling regulatory pathways may lead development new therapeutics.