Inhibition of Cellular Proliferation by Drug Targeting of Cyclin-Dependent Kinases

Abnormal cellular proliferation is associated with the pathology of several diseases, including cancer, atherosclerosis and restenosis post-angioplasty. Therefore, antiproliferative therapies may be a suitable approach to treat these disorders. Candidate targets for such strategies include specific components of the cell cycle machinery. Progression through the cell cycle in mammalian cells requires the activation of several cyclin-dependent protein kinases (CDKs) through their association with regulatory subunits called cyclins. Active CDK/cyclin holoenzymes phosphorylate cellular proteins including the retinoblastoma susceptibility gene product (pRb) and the related pocket proteins p107 and p130. Several compounds have been described that directly or indirectly inhibit the activity of CDKs, which results in a suppression of cell growth. In this review, we will discuss the use of drugs targeting CDKs and their therapeutic application in animal models and clinical trials.