Discovery of Rezatapopt (PC14586), a First-in-Class, Small-Molecule Reactivator of p53 Y220C Mutant in Development

p53 is a potent transcription factor that is crucial in regulating cellular responses to stress. Mutations in the <i>TP53</i> gene are found in >50% of human cancers, predominantly occurring in the DNA-binding domain (amino acids 94-292). The Y220C mutation accounts for 1.8% of all of the <i>TP53</i> mutations and produces a thermally unstable protein. Rezatapopt (also known as PC14586) is the first small-molecule p53 Y220C reactivator being evaluated in clinical trials. Rezatapopt was specifically designed to tightly bind to a pocket created by the <i>TP53</i> Y220C mutation. By stabilization of the p53 protein structure, rezatapopt restores p53 tumor suppressor functions. In mouse models with established human tumor xenografts harboring the <i>TP53</i> Y220C mutation, rezatapopt demonstrated tumor inhibition and regression at well-tolerated doses. In Phase 1 clinical trials, rezatapopt demonstrated a favorable safety profile within the efficacious dose range and showed single-agent efficacy in heavily pretreated patients with various <i>TP53</i> Y220C mutant solid tumors.