Format

Send to

Choose Destination
ACS Chem Biol. 2015 Feb 20;10(2):390-4. doi: 10.1021/cb500883h. Epub 2014 Dec 1.

Inhibition of CDC25B phosphatase through disruption of protein-protein interaction.

Author information

1
Department of Pathology, University of Michigan , 4510C MSRBI 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-5620, United States.

Abstract

CDC25 phosphatases are key cell cycle regulators and represent very attractive but challenging targets for anticancer drug discovery. Here, we explored whether fragment-based screening represents a valid approach to identify inhibitors of CDC25B. This resulted in identification of 2-fluoro-4-hydroxybenzonitrile, which directly binds to the catalytic domain of CDC25B. Interestingly, NMR data and the crystal structure demonstrate that this compound binds to the pocket distant from the active site and adjacent to the protein-protein interaction interface with CDK2/Cyclin A substrate. Furthermore, we developed a more potent analogue that disrupts CDC25B interaction with CDK2/Cyclin A and inhibits dephosphorylation of CDK2. Based on these studies, we provide a proof of concept that targeting CDC25 phosphatases by inhibiting their protein-protein interactions with CDK2/Cyclin A substrate represents a novel, viable opportunity to target this important class of enzymes.

PMID:
25423142
PMCID:
PMC4340349
DOI:
10.1021/cb500883h
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for American Chemical Society Icon for PubMed Central
Loading ...
Support Center