Development of CDK inhibitors as cancer therapeutics

Excerpt

The cyclin-dependent kinases form a large family of enzymes in human cells that are involved in the control of cell proliferation and transcription. A large number of small molecule inhibitors of this class of enzyme have been developed in both the pharmaceutical and academic communities, and at least two have entered clinical trial, having shown efficacy in preclinical models. Alterations in the activity of this class of enzymes is a frequent feature of human cancers, brought about by altered expression of either the enzymes themselves or their regulators such as p21, p27 and p16. The exact role of each of the different kinases has proved hard to determine as knockout mouse studies have implied a degree of redundancy and the exact substrates of each enzyme in vivo are still unclear. In addition, most of the current inhibitors are not specific to a single form of the enzyme and new regulatory pathways are still being discovered. Intense studies of one such inhibitor, R-Roscovitine (CYC202), including trials involving more than 100 patients, have established the potential of the class as non-genotoxic anti-cancer drugs. In some model systems the activity of this class of compound is best explained by their activity as inhibitors of transcriptional elongation, and a link between this mechanism and the induction of apoptosis has been established. The concept of cyclin-specific inhibitors as more sophisticated genetic models of target validation in this field will be discussed. …