FMC-220

FMC-220 is a first-in-class, highly selective covalent small molecule activator of the p53 Y220C mutant protein. It is designed to address the potency and durability limitations of non-covalent approaches targeting this specific TP53 mutation, which occurs in approximately 1–2% of cancers—most commonly in solid tumors such as lung, breast, ovarian, and colorectal cancer. The Y220C mutation destabilizes p53’s tumor-suppressive function; FMC-220 covalently binds to the mutant cysteine residue introduced by this substitution, stabilizing and reactivating p53. This leads to persistent promoter binding and sustained activation of the full p53 transcriptional response—even after treatment ends—resulting in durable anti-tumor activity through induction of cancer cell senescence and death. Preclinical studies have shown unprecedented potency at low doses across multiple tumor models (including those with KRAS co-mutations), with high selectivity for the target population. Developed using Frontier Medicines’ chemoproteomics-powered drug discovery platform, an IND filing is planned for late 2025[1][2][3][4][5][7][8].