Format

Send to

Choose Destination
See comment in PubMed Commons below
J Med Chem. 2006 Sep 7;49(18):5470-7.

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

Author information

1
Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.

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.

PMID:
16942020
DOI:
10.1021/jm060216x
[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for American Chemical Society
    Loading ...
    Support Center