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.

[1]  G L Trainor,et al.  Cyclin-dependent kinase inhibitors: useful targets in cell cycle regulation. , 2000, Journal of medicinal chemistry.

[2]  Paul Greengard,et al.  Pharmacological inhibitors of cyclin-dependent kinases. , 2002, Trends in pharmacological sciences.

[3]  Jane A. Endicott,et al.  Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor , 2002, Nature Structural Biology.

[4]  E. Sausville.  Complexities in the development of cyclin-dependent kinase inhibitor drugs. , 2002, Trends in molecular medicine.

[5]  I. Hardcastle,et al.  Designing inhibitors of cyclin-dependent kinases. , 2002, Annual review of pharmacology and toxicology.

[6]  David A. Fletcher,et al.  The United Kingdom Chemical Database Service , 1996, J. Chem. Inf. Comput. Sci..

[7]  L. Johnson,et al.  4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2. , 2003, Bioorganic & medicinal chemistry letters.

[8]  C. Sherr.  Cancer Cell Cycles , 1996, Science.

[9]  E. Sausville,et al.  Preclinical and clinical development of cyclin-dependent kinase modulators. , 2000, Journal of the National Cancer Institute.

[10]  M. Barbacid,et al.  To cycle or not to cycle: a critical decision in cancer , 2001, Nature reviews. Cancer.

[11]  L. Johnson,et al.  Probing the ATP ribose-binding domain of cyclin-dependent kinases 1 and 2 with O(6)-substituted guanine derivatives. , 2002, Journal of medicinal chemistry.

[12]  A H Calvert,et al.  Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles. , 2000, Journal of medicinal chemistry.