X-ray crystallographic studies of CDK2, a basis for cyclin-dependent kinase inhibitor design in anti-cancer drug research.
Inhibition of cyclin-dependent kinases is a theme of major interest in current anti-cancer agents research. Different classes of chemical inhibitors of these enzymes have been identified during the past decade and the structural basis of inhibition has been elucidated by X-ray crystallography studies of one member of the family, CDK2. In this article, we review the structural biology work that has led to a precise knowledge of the interactions between CDK2 and small organic molecules binding to its ATP pocket that are determinant for inhibitory activity. The use of this information to design or optimize CDK inhibitors by molecular modeling is also reviewed.
Furet
Pascal
P
Novartis Pharma Inc., Oncology Research Department, CH-4002 Basel, Switzerland. pascal.furet@pharma.novartis.com
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D042846:CDC2-CDC28 Kinases; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases