ATP-noncompetitive inhibitors of CDK-cyclin complexes.
Progression through the cell division cycle is controlled by a family of cyclin-dependent kinases (CDKs), the activity of which depends on their binding to regulatory partners (cyclins A-H). Deregulation of the activity of CDKs has been associated with the development of infectious, neurodegenerative, and proliferative diseases such as Alzheimer's, Parkinson's, or cancer. Most cancer cells contain mutations in the pathways that control the activity of CDKs. This observation led this kinase family to become a central target for the development of new drugs for cancer therapy. A range of structurally diverse molecules has been shown to inhibit the activity of CDKs through their activity as ATP antagonists. Nevertheless, the ATP binding sites on CDKs are highly conserved, limiting the kinase specificity of these inhibitors. Various genetic and crystallographic approaches have provided essential information about the mechanism of formation and activation of CDK-cyclin complexes, providing new ways to implement novel research strategies toward the discovery of new, more effective and selective drugs. Herein we review the progress made in the development of ATP-noncompetitive CDK-cyclin inhibitors.
Orzáez
Mar
M
Department of Medicinal Chemistry, Centro de Investigación Príncipe Felipe, Avda. Autopista del Saler 16, 46012, Valencia, Spain. morzaez@cipf.es
Gortat
Anna
A
Mondragón
Laura
L
Bachs
Oriol
O
Pérez-Payá
Enrique
E
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002453:Cell Cycle; D019295:Computational Biology; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016213:Cyclins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology
D000970:Antineoplastic Agents; D016213:Cyclins; D010455:Peptides; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D018844:Cyclin-Dependent Kinases