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

Abstract：

: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-cyclohexylmethoxy-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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Pratt DJ,Bentley J,Jewsbury P,Boyle FT,Endicott JA,Noble ME

doi

10.1021/jm060216x

subject

Has Abstract

pub_date

2006-09-07 00:00:00

pages

5470-7

issue

18

eissn

0022-2623

issn

1520-4804

journal_volume

49

pub_type

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