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N2-substituted O6-cyclohexylmethylguanine derivatives: Potent inhibitors of cyclin-dependent kinases 1 and 2

Lookup NU author(s): Dr Ian Hardcastle, Dr Christine Arris, Dr Johanne Bentley, Professor Nicola Curtin, Professor Jane Endicott, Dr Ashleigh Gibson, Professor Bernard Golding, Professor Roger Griffin, Dr Veronique Mesguiche, Professor Herbie Newell, Professor Martin Noble, Lan Wang, Hayley Whitfield

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Abstract

The adenosine 5′-triphosphate (ATP) competitive cyclin-dependent kinase inhibitor O6-cyclohexylmethylguanine (NU2058, 1) has been employed as the lead in a structure-based drug discovery program resulting in the discovery of the potent CDK1 and -2 inhibitor NU6102 (3, IC50 = 9.5 nM and 5.4 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). The SAR for this series have been explored further by the synthesis and evaluation of 45 N2-substituted analogues of NU2058. These studies have confirmed the requirement for the hydrogen bonding N2-NH group and the requirement for an aromatic N2-substituent to confer potency in the series. Additional potency is conferred by the presence of a group capable of donating a hydrogen bond at the 4′-position, for example, the 4′-hydroxy derivative (25, IC50 = 94 nM and 69 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), 4′-monomethylsulfonamide derivative (28, IC50 = 9 nM and 7.0 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), and 4′-carboxamide derivative (34, IC50 = 67 nM and 64 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). X-ray crystal structures have been obtained for key compounds and have been used to explain the observed trends in activity.


Publication metadata

Author(s): Hardcastle IR, Arris CE, Bentley J, Boyle FT, Chen Y, Curtin NJ, Endicott JA, Gibson AE, Golding BT, Griffin RJ, Jewsbury, P., Menyerol, J., Mesguiche, V., Newell, D.R., Noble, M., Pratt, D., Wang, L., Whitfield, H.J.

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2004

Volume: 47

Issue: 15

Pages: 3710-3722

Print publication date: 01/07/2004

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

URL: http://dx.doi.org/10.1021/jm0311442

DOI: 10.1021/jm0311442

PubMed id: 15239650


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