Structural Analysis of the CDK4/cyclin D1 Substrate Recognition Site and Basis for p27 and Inhibitor Binding

Reference #: 00829

An alternative strategy for inhibition of the cyclin dependent kinases in anti-tumor drug discovery is afforded through the substrate recruitment site on the cyclin positive regulatory subunit. This approach offers the potential for generating cell cycle-specific CDK inhibitors and to reduce the inhibition of transcription mediated through CDK7 and 9, commonly observed with ATP competitive compounds. While highly potent peptide and small molecule inhibitors of CDK2/cyclin A, E substrate recruitment have been reported, little information has been generated on the determinants of inhibitor binding in the cyclin groove of the CDK4/cyclin D1 complex. CDK4/cyclin D is a validated anti-cancer drug target and continues to be widely pursued in the development of new therapeutics based on cell cycle blockade.

Dr. Campbell McInnes and his research team have investigated the structural basis for peptide binding to the CDK4/cyclin D1 complex’s cyclin groove and examined the features contributing to potency and selectivity of inhibitors. The group synthesized Peptidic inhibitors of CDK4/cyclin D of pRb phosphorylation and generated their complexes with CDK4/cyclin D1 crystal structures.

• Identify unique aspects of cyclin D1 that have a significant impact on peptide interaction, and which can be exploited in the design of cyclin groove based CDK inhibitors

• Creation of chemical biology probes to determine the cellular and anti-tumor effects of CDK inhibitors which are cell cycle-specific and do not inhibit the transcriptional regulatory effects of other cyclin dependent kinases

Comparisons of the cyclin grooves of cyclin A2 and D1 provide insights in the determinants for peptide binding and the basis for differential binding and inhibition.

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http://www.ncbi.nlm.nih.gov/pubmed/20843055