title: Understanding and modulating cyclin-dependent kinase inhibitor specificity: molecular modeling and biochemical evaluation of pyrazolopyrimidinones as CDK2/cyclin A and CDK4/cyclin D1 inhibitors.
abstract: Cyclin-dependent kinases (CDKs) play a key role in regulating the cell cycle. The cyclins, their activating agents, and endogenous CDK inhibitors are frequently mutated in human cancers, making CDKs interesting targets for cancer chemotherapy. Our aim is the discovery of selective CDK4/cyclin D1 inhibitors. An ATP-competitive pyrazolopyrimidinone CDK inhibitor was identified by HTS and docked into a CDK4 homology model. The resulting binding model was consistent with available SAR and was validated by a subsequent CDK2/inhibitor crystal structure. An iterative cycle of chemistry and modeling led to a 70-fold improvement in potency. Small substituent changes resulted in large CDK4/CDK2 selectivity changes. The modeling revealed that selectivity is largely due to hydrogen-bonded interactions with only two kinase residues. This demonstrates that small differences between enzymes can efficiently be exploited in the design of selective inhibitors.
authors.affiliation: Pharmaceutical Research Institute, Bristol-Myers Squibb Company, 5400, Princeton, NJ 08543, USA. karen.rossi@bms.com
authors.forename: Karen A
authors.initials: KA
authors.lastname: Rossi
authors.forename: Jay A
authors.initials: JA
authors.lastname: Markwalder
authors.forename: Steven P
authors.initials: SP
authors.lastname: Seitz
authors.forename: Chong-Hwan
authors.initials: CH
authors.lastname: Chang
authors.forename: Sarah
authors.initials: S
authors.lastname: Cox
authors.forename: Michael D
authors.initials: MD
authors.lastname: Boisclair
authors.forename: Leonardo
authors.initials: L
authors.lastname: Brizuela
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Brenner
authors.forename: Pieter F W
authors.initials: PF
authors.lastname: Stouten
mesh_terms: D000595:Amino Acid Sequence; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D019925:Cyclin A / Q000037:antagonists & inhibitors*; D019938:Cyclin D1 / Q000037:antagonists & inhibitors*; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
chemical_list: D019925:Cyclin A; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D011744:Pyrimidinones; D019938:Cyclin D1; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases