Design of Cyclin Dependent Kinase 2 Inhibitors

Cyclin-dependent kinase 2 (CDK2) is a central regulator of cell cycle progression and appearsto act as a gate-keeper for the G1 to S phase transition. The three-dimensional structures of the CDK2apoenzyme as well as the CDK2-Mg2+ ATP complex have recently been determined to 2.4A resolution.We have also recently obtained diffractable co-crystals of CDK2 bound to two specific CDC2/CDK2inhibitors. We have completed the structure determination of the CDK2-inhibitor complexes and usedthis information for the design of more potent and selective inhibitors as antiproliferative therapeuticagents. Anti-cancer drugs which intervene by shutting off the pathways regulating cellular proliferationoffer the potential of a much less toxic approach to constraining unregulated cell growth.