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

p53 is a potent transcription\nfactor that is crucial in regulating\ncellular responses to stress. Mutations in the <i>TP53</i> gene are found in >50% of human cancers, predominantly occurring\nin the DNA-binding domain (amino acids 94–292). The Y220C mutation\naccounts for 1.8% of all of the <i>TP53</i> mutations and\nproduces a thermally unstable protein. Rezatapopt (also known as PC14586)\nis the first small-molecule p53 Y220C reactivator being evaluated\nin clinical trials. Rezatapopt was specifically designed to tightly\nbind to a pocket created by the <i>TP53</i> Y220C mutation.\nBy stabilization of the p53 protein structure, rezatapopt restores\np53 tumor suppressor functions. In mouse models with established human\ntumor xenografts harboring the <i>TP53</i> Y220C mutation,\nrezatapopt demonstrated tumor inhibition and regression at well-tolerated\ndoses. In Phase 1 clinical trials, rezatapopt demonstrated a favorable\nsafety profile within the efficacious dose range and showed single-agent\nefficacy in heavily pretreated patients with various <i>TP53</i> Y220C mutant solid tumors.