Restoration of the tumor suppressor function of tumor-associated p53 mutants, including the Y220C substitution, has posed a significant challenge for therapeutic discovery. In this study, 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 antiproliferative 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 antitumor activity in preclinical models as single agents and in combination with immunotherapy. Currently, rezatapopt is being evaluated in a registrational phase II clinical trial for patients with advanced solid tumors harboring the TP53 Y220C mutation. SIGNIFICANCE: Rezatapopt is a clinical-stage compound that offers a promising treatment option for TP53-mutant cancers. This study details the characterization of rezatapopt and its related compounds, which can reinstate the tumor suppressor activity of the p53 Y220C mutant. These results emphasize the potential for targeting p53 mutations in cancer therapy.