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Mutations in the TP53 gene are the most frequent somatic alterations in human cancer; approximately 50% of all human cancers possess mutations in TP53. Missense mutations in TP53 which result in a non-functional protein are the most frequently identified, these occur across the gene, however most hotspot mutations are localized within the DNA binding domain of the protein. Y220C is one such hotspot mutation, prevalent in ~1.8% of TP53 mutant tumors. PC14586 was structurally designed to bind tightly to a crevice within the mutant protein (KD~2.5 nM). It is the first orally bioavailable small molecule and selective reactivator of Y220C mutant p53 protein in clinical development. In Y220C mutant human cell lines, 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). PC14586 has favorable pharmaceutical properties in pre-clinical species. In nude mice bearing Y220C mutant NUGC3 gastric cancer xenograft tumors, oral administration of PC14586 results in a dose responsive anti-tumor effect, with a target efficacious dose of 100 mg/kg daily resulting in approximately 80% tumor regression after 3 weeks. This anti-tumor effect was driven by a dose responsive pharmacodynamic modulation of the mutant p53 target. In human xenografts, PC14586 was shown to convert Y220C mutant to the wildtype conformation, resulting in activation of p53 transcription. This was demonstrated by the measurement of a p53 mRNA transcriptional signature and at the protein level by increases in p21 and MDM2 in the tumor and Macrophage Inhibitory Cytokine-1 (MIC-1) in both the tumor and plasma. In a C57Bl/6J syngeneic xenograft model bearing the Y220C mutation, administration of PC14586 at 100 mg/kg orally resulted in complete tumor cure in 80% of mice. PC14586 is well tolerated by pre-clinical species and possesses a favorable development profile. The safety and efficacy of PC14586 is currently being evaluated in a seamless Phase I/II clinical study that is a biomarker driven, solid tumor agnostic trial with patients whose tumor bears the Y220C TP53 mutation (NCT study identifier NCT04585750). Citation Format: Melissa Dumble, Lizhong Xu, Romyr Dominique, Binbin Liu, Hong Yang, Mary-Kate McBrayer, Dafydd Thomas, Bruce Fahr, Hongju Li, Kuo-Sen Huang, Kimberly Robell, Chris Mulligan, Brandon Russo, Anna Puzio-Kuter, Thomas Davis, Binh Vu. PC14586: The first orally bioavailable small molecule reactivator of Y220C mutant p53 in clinical development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB006.