Structure-based design of 2-arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinases 1 and 2.
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.
Sayle
Kerry L
KL
Northern Institute for Cancer Research, School of Natural Sciences-Chemistry, Bedson Building, University of Newcastle, Newcastle Upon Tyne NE1 7RU, UK.
Bentley
Johanne
J
Boyle
F Thomas
FT
Calvert
A Hilary
AH
Cheng
Yuzhu
Y
Curtin
Nicola J
NJ
Endicott
Jane A
JA
Golding
Bernard T
BT
Hardcastle
Ian R
IR
Jewsbury
Philip
P
Mesguiche
Veronique
V
Newell
David R
DR
Noble
Martin E M
ME
Parsons
Rachel J
RJ
Pratt
David J
DJ
Wang
Lan Z
LZ
Griffin
Roger J
RJ
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
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