Clinical progress of selective cyclin-dependent kinase (CDK) inhibitors

Cyclin-dependent kinases (CDKs) are cellular proteins that control cell proliferation. Due to their central role in controlling cell growth and to their dysregulation in many cancers, CDKs have become an important molecular target for oncology drug development programs. The clinical progress of the first-generation compound alvocidib and three second-generation inhibitors (SNS-032, seliciclib and Ro-4584820) is reviewed here. In order to fully evaluate the clinical utility of these agents, dosing schedules and routes of administration continue to be optimized with the goals of minimizing toxicities and maximizing exposure. To date, single-agent phase II efficacy trials in cancer patients using alvocidib have been disappointing, possibly due to dosing limitations resulting from competing toxicities. Recent clinical results, however, indicate that alvocidib may still find niche utilities as single-agent therapy employing finely tailored dosing schedules for particularly susceptible cancers, such as chronic lymphocytic leukemia (CLL). Evaluation of second-generation compounds with greater potency, reduced toxicity and oral activity is continuing in single-agent trials. Clinical applications for combinations with other cytotoxic agents are also being pursued for both alvocidib and the second-generation agents. The clinical role of these agents continues to be explored, although the general clinical validation of the target in cancer therapy is possibly still several years away. In fact, these agents are more likely to be used clinically in combination with other cytotoxic agents than as stand-alone therapy.