Rezatapopt, also known as PC14586, is p53 Y220C reactivator that binds selectively to p53 Y220C mutant protein and restores the p53 wildtype conformation and transcriptional activity, resulting in potent preclinical antitumor activity. PC14586 was structurally designed to bind tightly to a crevice within the mutant protein (KD~2.5 nM). PC14586 was shown to stabilize the Y220C mutant in the wild type conformation, resulting in reactivation of p53 transcriptional activity and subsequent expression of its target proteins (e.g. p21, MDM2, Bax, PUMA). The reactivation of p53 function is highly selective to Y220C mutant cells and results in arrest of the cell cycle in vitro (IC50 ~0.230-1.8 μM). In nude mice bearing Y220C mutant NUGC3 gastric cancer xenograft tumors, oral administration of PC14586 results in a dose responsive anti-tumor effect. In human xenografts, PC14586 was shown to convert Y220C mutant to the wildtype conformation, resulting in activation of p53 transcription.
