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Lookup NU author(s): Dr Johanne Bentley,
Dr Christine Arris,
Professor Nicola CurtinORCiD,
Professor Jane Endicott,
Dr Ashleigh Gibson,
Emeritus Professor Bernard Golding,
Professor Roger Griffin,
Dr Ian HardcastleORCiD,
Dr Veronique Mesguiche,
Professor Herbie Newell,
Professor Martin NobleORCiD,
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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.
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
Print publication date: 01/10/2002
ISSN (print): 1072-8368
ISSN (electronic): 1545-9985
PubMed id: 12244298
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