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

Lookup NU author(s): Kerry Louise Sayle, Dr Johanne Bentley, Professor Hilary Calvert, Dr YuZhu Cheng, Professor Nicola CurtinORCiD, Professor Jane EndicottORCiD, Emeritus Professor Bernard Golding, Dr Ian HardcastleORCiD, Dr Veronique Mesguiche, Emeritus Professor Herbie Newell, Professor Martin NobleORCiD, Rachel Parsons, Lan Wang, Professor Roger Griffin

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Abstract

A series of O4-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 IC50 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. © 2003 Elsevier Ltd. All rights reserved.

Publication metadata

Author(s): Sayle, K., Bentley, J., Boyle, F., Calvert, A. H., Cheng, Y., Curtin, N. J., Endicott, J., Golding, B., Hardcastle, I., Jewsbury, P., Mesguiche, V., Newell, D. R., Noble, M., Parsons, R., Pratt, D., Wang, L., Griffin, R. J.

Publication type: Article

Publication status: Published

Journal: Bioorganic and Medicinal Chemistry Letters

Year: 2003

Volume: 13

Issue: 18

Pages: 3079-3082

Print publication date: 15/09/2003

ISSN (print): 0960-894X

ISSN (electronic): 1464-3405

URL: http://dx.doi.org/10.1016/S0960-894X(03)00651-6

DOI: 10.1016/S0960-894X(03)00651-6

PubMed id: 12941338

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