Recent advances and new directions in the discovery and development of cyclin-dependent kinase inhibitors.
The eukaryotic cell division cycle is coordinated by cyclin-dependent protein kinases (CDKs) and cyclin subunits specific for the different phases of the cycle. These complexes phosphorylate target substrates, including the retinoblastoma susceptibility gene product (pRb) and related proteins. Cellular neoplastic transformations are accompanied by loss of regulation of cell cycle checkpoints, frequently through aberrant expression of CDKs and cyclins, as well as loss or mutation of their negative regulators. Consequently, one strategy in the development of mechanism-based anticancer therapeutics has been to halt malignant cellular proliferation through inhibition of the enzymatic activity of CDKs. The development of inhibitors selective for the ATP binding sites of particular protein kinases is a comparatively recent medicinal chemistry endeavor. Advances relevant to CDK inhibition are reviewed critically and alternative approaches to CDK inhibition, as well as applications of CDK inhibitors to therapeutic areas other than oncology, are also discussed.
Fischer
P M
PM
Cyclacel Ltd., James Lindsay Place, Dundee, DD1 5JJ, Scotland, UK. pfischer@cyclacel.com
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D013329:Structure-Activity Relationship; D013698:Templates, Genetic
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018844:Cyclin-Dependent Kinases