Small molecule inhibitors targeting cyclin-dependent kinases as anticancer agents.

Cyclin-dependent kinases (CDKs) and their related pathways represent some of the most attractive targets in the development of anticancer therapeutics. Among a variety of CDK inhibitors under development, flavopiridol, UCN-01, CYC202, and BMS-387032 are undergoing clinical evaluation based on evidence of preclinical antitumor activity. Flavopiridol exerts multiple effects in tumor cells, including inhibition of multiple CDKs, transcriptional inhibition secondary to disruption of P-TEFb (CDK9/cyclin T), induction of apoptosis, and antiangiogenesis. UCN-01 was initially developed as a protein kinase C (PKC) inhibitor, but its major antitumor effects appear to be related to CDK inhibition or "inappropriate" activation of cdc2/CDK1 abrogating the G2 and S checkpoints, inhibition of PDK1/Akt, and induction of apoptosis through a PKC-independent mechanism. Significantly, combining these CDK inhibitors with either conventional cytotoxic drugs or novel agents targeting signal transduction pathways can markedly enhance antitumor activity, particularly induction of apoptosis, in various preclinical models. Such findings may serve as a basis for the introduction of novel combination regimens into clinical trials.