Inhibition of CDKs as a therapeutic modality

Altered cell cycle control has emerged as a recurring theme in neoplasia. Strategies that would return toward normal the altered cell cycle control present in tumor cells have appeal as novel approaches to cancer treatment. Cyclin-dependent kinases (CDKs) control the progression through the cell cycle, operating at the transition from the G2 to M and G1 to S phases, and progression through S. CDKs are regulated by a complex set of mechanisms, including the presence of activating cyclins, regulatory phosphorylations, and endogenous CDK inhibitors at "checkpoints." This overview focuses on progress in defining compounds that can antagonize directly the action of CDKs. These have emerged as various types of ATP site-directed inhibitors, including flavopiridol, N-substituted adenine derivatives, the natural product butyrolactone, staurosporine derivatives, and, more recently, the synthetic paullones. Paullones appear to be of interest in that one of the most active members of the class, 9-nitropaullone (alsterpaullone), requires relatively brief periods of exposure to living cells in order to effect lasting effects on cellular and proliferative potential. Two of these compounds, flavopiridol and UCN-01 (7-hydroxy-staurosporine), have entered early clinical trials and achieved concentrations that might potentially modulate CDK function. In the case of UCN-01, unexpected human plasma protein binding might prevent direct inhibition of CDKs but allow drug concentrations to be achieved that indirectly affect CDKs by checkpoint abrogation. Further studies with CDK inhibitors should define the expected end point of CDK inhibition more clearly in preclinical models and clinical systems, including cytostasis, apoptosis, or differentiation.