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Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor

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

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Abstract

Aberrant control of cyclin-dependent kinases (CDKs) is a central feature of the molecular pathology of cancer. Iterative structure-based design was used to optimize the ATP-competitive inhibition of CDK1 and CDK2 by O6-cyclohexylmethylguanines, resulting in O6-cyclohexylmethyl-2-(4′sulfamoylanilino)purine. The new inhibitor is 1,000-fold more potent than the parent compound (Ki values for CDK1 = 9 nM and CDK2 = 6 nM versus 5,000 nM and 12,000 nM, respectively, for O6-cyclohexylmethylguanine). The increased potency arises primarily from the formation of two additional hydrogen bonds between the inhibitor and Asp 86 of CDK2, which facilitate optimum hydrophobic packing of the anilino group with the specificity surface of CDK2. Cellular studies with O6-cyclohexylmethyl-2-(4′-sulfamoylanilino) purine demonstrated inhibition of MCF-7 cell growth and target protein phosphorylation, consistent with CDK1 and CDK2 inhibition. The work represents the first successful iterative synthesis of a potent CDK inhibitor based on the structure of fully activated CDK2-cyclin A. Furthermore, the potency of O6-cyclohexylmethyl-2-(4′-sulfamoylanilino)purine was both predicted and fully rationalized on the basis of protein-ligand interactions.


Publication metadata

Author(s): Davies T, Bentley J, Arris CE, Boyle FT, Curtin NJ, Endicott J, Gibson A, Golding BT, Griffin RJ, Hardcastle IR, Jewsbury, P., Johnson, L., Mesguiche, V., Newell, D.R., Noble, M., Tucker, J.A., Wang, L., Whitfield, H.J.

Publication type: Article

Publication status: Published

Journal: Nature Structural Biology

Year: 2002

Volume: 9

Issue: 10

Pages: 745-749

Print publication date: 01/10/2002

ISSN (print): 1072-8368

ISSN (electronic): 1545-9985

URL: http://dx.doi.org/10.1038/nsb842

DOI: 10.1038/nsb842

PubMed id: 12244298


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