title: Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics.
abstract: Cyclin-dependent kinases (CDKs) have been considered promising drug targets for a number of years, but most CDK inhibitors have failed rigorous clinical testing. Recent studies demonstrating clear anticancer efficacy and reduced toxicity of CDK4/6 inhibitors such as palbociclib and multi-CDK inhibitors such as dinaciclib have rejuvenated the field. Favorable results with palbociclib and its recent U.S. Food and Drug Administration approval demonstrate that CDK inhibitors with narrow selectivity profiles can have clinical utility for therapy based on individual tumor genetics. A brief overview of results obtained with ATP-competitive inhibitors such as palbociclib and dinaciclib is presented, followed by a compilation of new avenues that have been pursued toward the development of novel, non-ATP-competitive CDK inhibitors. These creative ways to develop CDK inhibitors are presented along with crystal structures of these agents complexed with CDK2 to highlight differences in their binding sites and mechanisms of action. The recent successes of CDK inhibitors in the clinic, combined with the potential for structure-based routes to the development of non-ATP-competitive CDK inhibitors, and evidence that CDK inhibitors may have use in suppressing chromosomal instability and in synthetic lethal drug combinations inspire optimism that CDK inhibitors will become important weapons in the fight against cancer.
authors.affiliation: Departments of Pharmacology and Therapeutics (M.E.L., P.E.C., B.K.L.), Anatomy and Cell Biology (S.N.), and the University of Florida Health Cancer Center (M.E.L., P.E.C., S.N., B.K.L.), University of Florida, Gainesville, Florida bklaw@ufl.edu.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Law
authors.affiliation: Departments of Pharmacology and Therapeutics (M.E.L., P.E.C., B.K.L.), Anatomy and Cell Biology (S.N.), and the University of Florida Health Cancer Center (M.E.L., P.E.C., S.N., B.K.L.), University of Florida, Gainesville, Florida.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Corsino
authors.affiliation: Departments of Pharmacology and Therapeutics (M.E.L., P.E.C., B.K.L.), Anatomy and Cell Biology (S.N.), and the University of Florida Health Cancer Center (M.E.L., P.E.C., S.N., B.K.L.), University of Florida, Gainesville, Florida.
authors.forename: Satya
authors.initials: S
authors.lastname: Narayan
authors.affiliation: Departments of Pharmacology and Therapeutics (M.E.L., P.E.C., B.K.L.), Anatomy and Cell Biology (S.N.), and the University of Florida Health Cancer Center (M.E.L., P.E.C., S.N., B.K.L.), University of Florida, Gainesville, Florida bklaw@ufl.edu.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Law
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D043171:Chromosomal Instability; D003497:Cyclic N-Oxides; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D006801:Humans; D007212:Indolizines; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D007212:Indolizines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011726:Pyridinium Compounds; C553669:dinaciclib; D018844:Cyclin-Dependent Kinases; C500026:palbociclib