Restoration of the Tumor Suppressor Function of Y220C-Mutant p53 by Rezatapopt, a Small Molecule Reactivator

Abstract Restoration of the tumor suppressor function of tumor-associated p53 mutants, including the Y220C substitution, has posed a significant challenge for therapeutic discovery. Here, we describe rezatapopt (PC14586), part of a series of compounds designed to reactivate the p53 Y220C mutant. These compounds restore p53 tumor suppressor function by correcting its conformation and enabling it to bind DNA and activate downstream target genes, thus inducing anti-proliferative changes in tumor cells. Our findings are supported by biochemical and structural analysis, in vitro and in vivo transcriptomics, and functional data, revealing the recovery of multiple aspects of the wild type p53 program. These compounds demonstrate potent anti-tumor activity in preclinical models as single agents and in combination with immunotherapy. Currently, rezatapopt is being evaluated in a registrational Phase 2 clinical trial for patients with advanced solid tumors harboring the TP53 Y220C mutation.