Designing Inhibitors of Cyclin-Dependent Kinases

Cyclin-dependent kinases (cdks) play a pivotal role in controlling progression through the cell cycle. The complex mechanisms that control cdks have been elucidated and, in the case of cdk2, explained with reference to X-ray crystal structures of the catalytically active and inactive kinase. Deregulation of the cell cycle is commonly observed in cancer, so cdks are potential targets for experimental therapeutic agents. A number of distinct structural classes of cdk inhibitors have been discovered. Good selectivity among these ATP competitive inhibitors for cdks over other kinases has been established, and selectivity between individual cdks is often observed. The crystal structures of a number of key inhibitors bound to cdk2 can be used to explain the observed structure-activity relationships within the compound series and to guide the design of more potent inhibitors.