Abstract 1716: A small molecule corrector for p53 mutants found in cancer

Abstract

Abstract p53 is the main tumor suppressor protein in vertebrates and the most frequently mutated gene in human cancers. The majority of p53 mutations are missense mutations resulting in the expression of full-length p53 with inactive tumor suppressor function. Small molecule corrector drugs that change the mutant p53 conformation to a wild-type-like structure are attractive goals for personalized, targeted cancer therapies. Our previous work has shown that restoring p53 activities represses cancer cells and tumor growth in vitro and in vivo. This and other work suggest that reactivation of p53 could have therapeutic potential for cancer patients with mutated p53. This study aims to investigate a new potential p53 corrector small molecule, UCI-1001. Our data suggest that treatment of p53 mutant cancer cell lines with compounds of the UCI-1001 series inhibits cell growth in a p53 mutant-dependent manner and induces some p53-wild-type like activities such as mutant p53 DNA binding, transcriptional activation of p53 target genes, and induction of cell death. Utilizing the cellular thermal shift assay, CETSA, we show that UCI-1001 binds mutant p53 in vivo and changes mutant p53 conformation to a wild-type-like structure. Taken together, these preliminary results suggest the UCI-1001 series is a promising candidate for the development of p53 corrector drugs, but further development of pharmacokinetic properties will be necessary for translation to the bedside. Citation Format: Maryam Mohammed J Fallatah, Özlem Demir, Rommie Amaro, Peter Kaiser. A small molecule corrector for p53 mutants found in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1716.