A novel class of cyclin-dependent kinase inhibitors identified by molecular docking act through a unique mechanism

Patrick Corsino, Nicole Horenstein, David Ostrov, Thomas Rowe, Mary Law, Amanda Barrett, George Aslanidi, W. Douglas Cress, Brian Law

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)29945-29955
Number of pages11
JournalJournal of Biological Chemistry
Volume284
Issue number43
DOIs
StatePublished - Oct 23 2009
Externally publishedYes

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