The p53 protein plays a major role in cancer prevention, and over 50% of cancer diagnoses can be attributed to p53 malfunction.1 One destabilizing p53 mutation, Y220C, causes local protein unfolding and ultimately results in loss of Zn in the DNA-binding domain. The Y220C mutation also creates a druggable surface that many aim to stabilize using small molecules.2 We are developing small molecule stabilizers of p53 Y220C that feature Zn-binding fragments to chaperone Zn to the metal depleted site and restore wild-type function.3,4,5 This presentation describes the design and synthesis of a series of ligands containing phenols for interaction and stabilization of the p53-Y220C surface cavity, and Zn-binding fragments for metallochaperone activity. We characterized their Zn-binding affinity using spectroscopic methods, while in vitro cytotoxicity showed that a number of analogues display equal or higher in vitro cytotoxicity in comparison to the front-line drug cisplatin. These lead compounds also show Y220C mutant-specific induction of apoptosis, and recover p53 transcriptional function in the NUGC3 cell line. Recent results will be presented, including inhibition of mutant p53 aggregation.

Multifunctional molecules for reactivation of mutant p53

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.