Pharmacophore-guided discovery of CDC25 inhibitors causing cell cycle arrest and tumor regression.

ABSTRACT: CDC25 phosphatases play a key role in cell cycle transitions and are important targets for cancer therapy. Here, we set out to discover novel CDC25 inhibitors. Using a combination of computational methods, we defined a minimal common pharmacophore in established CDC25 inhibitors and performed virtual screening of a proprietary library. Based on the availability of crystal structures for CDC25A and CDC25B, we implemented a molecular docking strategy and carried out hit expansion/optimization. Enzymatic assays revealed that naphthoquinone scaffolds were the most promising CDC25 inhibitors among selected hits. At the molecular level, the compounds acted through a mixed-type mechanism of inhibition of phosphatase activity, involving reversible oxidation of cysteine residues. In 2D cell culture

SUBMITTER: Kabakci Z 

PROVIDER: S-EPMC6362118 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature