Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors.

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Gray NS, Wodicka L, Thunnissen AM, Norman TC, Kwon S, Espinoza FH, Morgan DO, Barnes G, LeClerc S, Meijer L, Kim SH, Lockhart DJ, Schultz PG

Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors.

Science. 1998 Jul 24;281(5376):533-8.

PubMed ID
9677190 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Cyclin-dependent kinase 2P24941Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
PurvalanolCyclin-dependent kinase 2IC 50 (nM)6N/AN/ADetails
PurvalanolCyclin-dependent kinase 2IC 50 (nM)9N/AN/ADetails
PurvalanolCyclin-dependent kinase 4IC 50 (nM)>10000N/AN/ADetails
PurvalanolMitogen-activated protein kinase 3IC 50 (nM)3333N/AN/ADetails