Structure-based design of 2-arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinases 1 and 2.

Article Details

Citation

Sayle KL, Bentley J, Boyle FT, Calvert AH, Cheng Y, Curtin NJ, Endicott JA, Golding BT, Hardcastle IR, Jewsbury P, Mesguiche V, Newell DR, Noble ME, Parsons RJ, Pratt DJ, Wang LZ, Griffin RJ

Structure-based design of 2-arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinases 1 and 2.

Bioorg Med Chem Lett. 2003 Sep 15;13(18):3079-82.

PubMed ID
12941338 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
4-{[4-AMINO-6-(CYCLOHEXYLMETHOXY)-5-NITROSOPYRIMIDIN-2-YL]AMINO}BENZAMIDECyclin-dependent kinase 2IC 50 (nM)347.530Details
6-CYCLOHEXYLMETHYLOXY-5-NITROSO-PYRIMIDINE-2,4-DIAMINECyclin-dependent kinase 2IC 50 (nM)22007.530Details
O6-CYCLOHEXYLMETHOXY-2-(4'-SULPHAMOYLANILINO) PURINECyclin-dependent kinase 2IC 50 (nM)5.47.530Details