Abstract 3787: Restoring the function of the guardian of the genome: FMC-220 a highly potent and selective covalent activator of p53 Y220C

Loss of function mutations of the TP53 gene are the most common genetic defects across all human cancers. These mutations have long been intractable to drug development. The p53 Y220C mutation is common, occurring in ∼1% of cancers, leading to destabilization, aggregation and loss of p53 protein function. Application of the FrontierTM platform, which integrates chemoproteomics, machine-learning, and covalent fragment-based drug discovery, enabled the discovery of FMC-220, a potential first-in-class covalent activator of p53 Y220C, which is highly potent and selective in restoring p53 tumor suppressor function. FMC-220 works by forming an irreversible covalent bond with the mutant cysteine at amino acid 220 stabilizing the structure of the central p53 DNA binding domain. The covalent mechanism of action of FMC-220 delivers potent and durable induction of p53 transcriptional response that includes upregulation of known regulators of cell cycle arrest, senescence and cell death. In contrast to reversible Y220C binders including rezatapopt, covalent engagement of Y220C results in persistent activation of p53 following drug washout that leads to enhanced Y220C mutant cancer cell senescence and death. The exquisite selectivity of FMC-220 was confirmed through chemoproteomic analysis and knock-out of the Y220C allele demonstrating drug action is through modification of the Y220C mutant form of p53. Importantly, the action of FMC-220 is specific for the Y220C mutant form of the p53 protein, sparing any effect on wild-type p53 function. FMC-220 inhibits tumor cell viability with ∼100-fold increased potency relative to rezatapopt across a panel of Y220C mutant cell lines including in tumor cells with a KRAS co-mutation and irrespective of histology. This translates into potent pharmacodynamic activity and tumor regression in Y220C mutant CDX and PDX models in vivo. In addition, FMC-220 is very well tolerated in vivo. Together, these data demonstrate the promise of FMC-220, a first-in-class covalent activator of p53 Y220C, with the potential to deliver improved outcomes for patients with Y220C mutation positive tumors. Citation Format: John-Paul Upton, Irina Dotsenko, Vikram Narayan, Marya Liimatta, Jessica Paredes, Mikayla Shanafelt, Brian Tran, Svetlana Kholodar, Kyle Anderson, Tiep Le, Sarah Gilfillan, Shefali Sabhlok, Ziwei Hu, Reed Stein, Evan McMahon, Weiru Wang, Yan Wang, Snahel Patel, Lata Jayaraman, David Sperandio, Kevin R. Webster. Restoring the function of the guardian of the genome: FMC-220 a highly potent and selective covalent activator of p53 Y220C [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3787.