Chapter 17. Chemical Inhibitors of Cyclin-dependent Kinases

Publisher Summary Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that are composed of a catalytic CDK subunit and a regulatory cyclin subunit. Presently, eight CDKs and ten cyclins have been identified. CDK activity is regulated by many mechanisms, reflecting their critical role in cell cycle control. The cyclin subunit is the key regulator of CDK activity, with each CDK, interacting with a specific subset of cyclins. These subunits are cyclin A (CDK1, CDK2), B1–B3 (CDK1), C (CDK8), D1–D3 (CDK2, CDK4, CDK5, CDK6), E (CDK2), and H (CDK7). Phosphorylation of Thr of CDK1 is necessary for maximal kinase activity and phosphorylation of Thr and Tyr residues negatively regulate kinase activity. The dual specificity phosphatase Cdc25 dephosphorylates, Thr and Tyr, to produce active kinase. Another major mechanism of CDK regulation involves a diverse family of CDK inhibitory proteins, termed the CDls or CKls that bind and inactivate CDK-cyclin complexes. Research has started to highlight the connections between CDK regulation and cancer. Over expression of specific cyclins, particularly cyclin D 1 , can contribute to cell transformation and CDls have been identified as potential tumor suppressor genes. The p16 gene, in particular, is lost in the majority of tumor cell lines and in a significant number of primary tumors. The importance of CDKs and their regulators in cell cycle control, coupled with their frequent deregulation in cancer, makes them attractive targets for the identification of anti-neoplastic agents. In fact, a number of chemical inhibitors of CDK kinase activity have already been identified.