期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 284, 期 43, 页码 29945-29955出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.055251
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资金
- National Institutes of Health [R01-CA93651, CA119997]
- Florida Department of Health [07BB-8, 09BB-10, 08BB-05]
- Susan G. Komen for the Cure [KG080510]
The cyclin-dependent kinase (Cdk) family is emerging as an important therapeutic target in the treatment of cancer. Cdks 1, 2, 4, and 6 are the key members that regulate the cell cycle, as opposed to Cdks that control processes such as transcription (Cdk7 and Cdk9). For this reason, Cdks 1, 2, 4, and 6 have been the subject of extensive cell cycle-related research, and consequently many inhibitors have been developed to target these proteins. However, the compounds that comprise the current list of Cdk inhibitors are largely ATP-competitive. Here we report the identification of a novel structural site on Cdk2, which is well conserved between the cell cycle Cdks. Small molecules identified by a high throughput in silico screen of this pocket exhibit cytostatic effects and act by reducing the apparent protein levels of cell cycle Cdks. Drug-induced cell cycle arrest is associated with decreased Rb phosphorylation and decreased expression of E2F-dependent genes. Multiple lines of evidence indicate that the primary mechanism of action of these compounds is the direct induction of Cdk1, Cdk2, and Cdk4 protein aggregation.
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