Small Molecule Reactivator of p53 Y220C Mutant

Mutant p53 is one of the most attractive targets for new anti-cancer drugs. Although traditionally regarded as difficult to drug, several new strategies have recently become available for targeting the mutant protein. One of the most promising of these involves the use of low molecular weight compounds that promote refolding and reactivation of mutant p53 to its wild-type form.

WuXi AppTec recently contributed to a research article in ACS Med. Chem. Letters describing chemistry efforts that led to the discovery of PC14586, an orally available small molecule structural corrector that is designed to bind selectively to the pocket within the p53 Y220C mutant protein. In mouse models with established human tumor xenografts harboring the p53 Y220C mutation, this compound demonstrated tumor inhibition and regression at well-tolerated doses.