• Sustained reactivation of mutant p53 drives durable anti-tumor activity across models, including KRAS co-mutant tumors
• FMC-220 selectively stabilizes p53 Y220C at lower doses, overcoming key limitations of non-covalent approaches
• Addresses a defined patient population with high unmet need; IND filing on track for 2H 2025
  

BOSTON and SOUTH SAN FRANCISCO, Calif. – Frontier Medicines Corporation, a clinical-stage precision medicine company seeking to unlock the proteome to advance transformational therapies, today presented new preclinical data on FMC-220, a first-in-class covalent activator of p53 Y220C, at the American Association for Cancer Research (AACR) Annual Meeting 2025 in Chicago, Illinois. FMC-220 is designed to address the potency and durability challenges seen with non-covalent approaches targeting the structurally destabilized p53 Y220C mutant. Preclinical studies showed FMC-220 delivers unprecedented potency, selective engagement, and durable anti-tumor activity at low doses across a broad range of tumor models, including those harboring co-mutations such as those in KRAS. The company plans to file an Investigational New Drug (IND) application for FMC-220 in the second half of 2025.

“These data reinforce the promise of FMC-220 and the continued strength of the Frontier™ Platform to solve tough problems in drug discovery,” said Chris Varma, Ph.D., co-founder, chairman, and chief executive officer of Frontier Medicines. “FMC-220’s novel covalent mechanism cracked the p53 potency barrier seen with non-covalent approaches to deliver a durable benefit regardless of KRAS co-mutations and across multiple tumor types, driving value for patients. We believe FMC-220 has transformative potential as a tumor-agnostic therapy and we look forward to rapidly advancing this program toward the clinic later this year.”

FMC-220 covalently binds the mutant cysteine residue introduced by the Y220C substitution in TP53. TP53 is a common missense mutation found in approximately 1-2% of cancers, particularly prevalent in solid tumors such as lung, breast, ovarian and colorectal cancers. This mutation destabilizes the p53 protein—often referred to as the “guardian of the genome”—and impairs its tumor-suppressive functions, contributing significantly to cancer progression.

“FMC-220 effectively reactivates p53 Y220C by covalently stabilizing the mutant protein, leading to persistent promoter binding and sustained activation of the full p53 transcriptional response, even after treatment ends,” said Kevin Webster, Ph.D., chief scientific officer of Frontier Medicines. “Notably, unlike agents that cause reversible cell cycle arrest, FMC-220 activates cancer cell-death pathways and remains highly active in the presence of elevated MDM2 levels, a driver of resistance in tumors with RAS mutations. These promising results underscore FMC-220’s potential to offer lasting therapeutic benefits for patients with p53 Y220C-driven cancers.”

FMC-220 was discovered using the Frontier™ Platform, integrating chemoproteomics, covalent fragment-based discovery, and machine learning. FMC-220 is the second potential first-in-class program to advance from the platform, following FMC-376, a dual ON/OFF KRASG12C inhibitor currently in clinical development.

Presentation details follow:

Title: Restoring the function of the guardian of the genome: FMC-220, a highly potent and selective covalent activator of p53 Y220C
Presenter: Kevin Webster, Ph.D., Chief Scientific Officer
Date: April 28, 2025
Session: Novel Tumor Agents 
Location: AACR Annual Meeting 2025, Chicago, IL

About Frontier Medicines

Frontier Medicines is a clinical stage precision medicine company pioneering groundbreaking medicines to transform treatment for genetically-defined patient populations, starting with oncology and immunology. Our proprietary chemoproteomics powered drug discovery engine, the Frontier™ Platform, leverages covalent chemistry and machine learning to unlock hard-to-treat disease causing proteins for drug development. Today, we are advancing a diversified pipeline of wholly-owned precision medicines against the most important drivers of cancer and high-value immunology programs. Our lead candidate, FMC-376, is a dual inhibitor of ON+OFF KRAS^G12C. FMC-376 is a potential best-in-class therapy designed to completely block both forms of the KRAS mutation to overcome the lack of response and resistance seen with single-acting KRAS^G12C inhibitors. The Frontier™ Platform also enabled the discovery of FMC-220, the first covalent p53Y220C activator, designed to overcome the limitations of potency and durability seen in non-covalent approaches. For more information, please visit www.frontiermeds.com. Follow Frontier on LinkedIn.