title: Structure-based design of 2-arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinases 1 and 2.
abstract: A series of O(4)-cyclohexylmethyl-5-nitroso-6-aminopyrimidines bearing 2-arylamino substituents was synthesised and evaluated for CDK1 and CDK2 inhibitory activity. Consistent with analogous studies with O(6)-cyclohexylmethylpurines, 2-arylaminopyrimidines with a sulfonamide or carboxamide group at the 4'-position were potent inhibitors, with IC(50) values against CDK2 of 1.1+/-0.3 and 34+/-8 nM, respectively. The crystal structure of the 4'-carboxamide derivative, in complex with phospho-Thr160 CDK2/cyclin A, confirmed the expected binding mode of the inhibitor, and revealed an additional interaction between the carboxamide function and an aspartate residue.
authors.affiliation: Northern Institute for Cancer Research, School of Natural Sciences-Chemistry, Bedson Building, University of Newcastle, Newcastle Upon Tyne NE1 7RU, UK.
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Sayle
authors.forename: Johanne
authors.initials: J
authors.lastname: Bentley
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Boyle
authors.forename: A Hilary
authors.initials: AH
authors.lastname: Calvert
authors.forename: Yuzhu
authors.initials: Y
authors.lastname: Cheng
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.forename: Jane A
authors.initials: JA
authors.lastname: Endicott
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hardcastle
authors.forename: Philip
authors.initials: P
authors.lastname: Jewsbury
authors.forename: Veronique
authors.initials: V
authors.lastname: Mesguiche
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.forename: Martin E M
authors.initials: ME
authors.lastname: Noble
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Parsons
authors.forename: David J
authors.initials: DJ
authors.lastname: Pratt
authors.forename: Lan Z
authors.initials: LZ
authors.lastname: Wang
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors*; D051357:Cyclin-Dependent Kinase 2; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2