The pursuit for drugs that inhibit cyclin-dependent kinases (CDKs) has been an intense area of research for more than 15 years. CDKs are serine/threonine kinases that regulate cell cycle progression in a coordinated fashion. The cyclin-dependent kinase (CDK) family has received special attention due to their function as sensors of the mitogenic signals and their central role in cell proliferation. These kinases are frequently upregulated in human cancer mostly due to overexpression of their cyclin partners or inactivation of the CDK inhibitors. CDK inhibitors have the potential to induce cell cycle arrest and apoptosis in cancer cells. The first-generation inhibitors, Flavopiridol and CY-202, are in late-stage clinical trials, but so far have demonstrated only modest activity. Several new CDK inhibitors are entering the clinic. CDK1, CDK2, and CDK4 have mainly been targeted for small-molecule inhibitor development. Others of the CDK inhibitors recently entering clinical trials also inhibit CDK5, CDK7, and CDK9, which have functions not directly involving the cell cycle. Although significant progress has been made in targeting the CDKs, questions about the importance of CDK selectivity for effective tumor growth inhibition (TGI) remain. Absolute selectivity may not be the best approach to treat complex disorders where multiple pathways are deregulated, and combinations of effects might provide for better therapeutic agents. A broad-spectrum CDK inhibitor that selectively inhibits several CDKs may have enhanced antitumor activity.

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