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Dissecting the determinants of cyclin-dependent kinase 2 and cyclin-dependent kinase 4 inhibitor selectivity

Lookup NU author(s): Dr Johanne Bentley, Professor Jane Endicott, Professor Martin NobleORCiD


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Cyclin dependent kinases are a key family of kinases involved in cell cycle regulation and are an attractive target for cancer chemotherapy. The roles of four residues of the cyclin-dependent kinase active site in inhibitor selectivity were investigated by producing cyclin-dependent kinase 2 mutants bearing equivalent cyclin-dependent kinase 4 residues, namely F82H, L83V, H84D, and K89T. Assay of the mutants with a cyclin-dependent kinase 4-selective bisanilinopyrimidine shows that the K89T mutation is primarily responsible for the selectivity of this compound. Use of the cyclin-dependent kinase 2-selective 6-cyclo-hexylmethoxy-2-(4′-sulfamoylanilino)purine (NU6102) shows that K89T has no role in the selectivity, while the remaining three mutations have a cumulative influence. The results indicate that certain residues that are not frequently considered in structure-aided kinase inhibitor design have an important role to play. © 2006 American Chemical Society.

Publication metadata

Author(s): Pratt DJ, Bentley J, Jewsbury P, Boyle FT, Endicott JA, Noble MEM

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2006

Volume: 49

Issue: 18

Pages: 5470-5477

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society


DOI: 10.1021/jm060216x

PubMed id: 16942020


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