title: Structural determinants of CDK4 inhibition and design of selective ATP competitive inhibitors.
abstract: A number of selective inhibitors of the CDK4/cyclin D1 complex have been reported recently. Due to the absence of an experimental CDK4 structure, the ligand and protein determinants contributing to CDK4 selectivity are poorly understood at present. Here, we report the use of computational methods to elucidate the characteristics of selectivity and to derive the structural basis for specific, high-affinity binding of inhibitors to the CDK4 active site. From these data, the hypothesis emerged that appropriate incorporation of an ionizable function into a CDK2 inhibitor results in more favorable binding to CDK4. This knowledge was applied to the design of compounds in the otherwise CDK2-selective 2-anilino-4-(thiazol-5-yl)pyrimidine pharmacophore that are potent and highly selective ATP antagonists of CDK4/cyclin D1. The findings of this study also have significant implications in the design of CDK4 mimic structures based on CDK2.
authors.affiliation: Cyclacel Limited, James Lindsay Place, Dundee Technopole, Dundee DD1 5JJ, Scotland, UK. cmcinnes@cyclacel.com
authors.forename: Campbell
authors.initials: C
authors.lastname: McInnes
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
authors.forename: Sian
authors.initials: S
authors.lastname: Anderson
authors.forename: Janice
authors.initials: J
authors.lastname: O'Boyle
authors.forename: Wayne
authors.initials: W
authors.lastname: Jackson
authors.forename: George
authors.initials: G
authors.lastname: Kontopidis
authors.forename: Christopher
authors.initials: C
authors.lastname: Meades
authors.forename: Mokdad
authors.initials: M
authors.lastname: Mezna
authors.forename: Mark
authors.initials: M
authors.lastname: Thomas
authors.forename: Gavin
authors.initials: G
authors.lastname: Wood
authors.forename: David P
authors.initials: DP
authors.lastname: Lane
authors.forename: Peter M
authors.initials: PM
authors.lastname: Fischer
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D001667:Binding, Competitive / Q000187:drug effects; D018360:Crystallography, X-Ray; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000255:Adenosine Triphosphate; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases