Abstract 6974: Identification of a potent KRAS (ON) inhibitor with selectivity for mutant KRAS over HRAS and NRAS

Abstract Oncogenic KRAS gene mutations are prevalent across human cancers, including: pancreatic, lung, and colorectal. In the US alone, it is estimated that over 165, 000 cancer patients are affected by KRAS mutations annually. Early successes in the discovery of mutation specific therapeutics for KRAS led to the development of marketed agents adagrasib and sotorasib, which selectively inhibit KRASG12C. While these precision medicines address a critical unmet medical need, they only treat ∼11% of patients with oncogenic KRAS mutations. Recent efforts to address this disparity have resulted in the identification of pan KRAS inhibitors that target all clinically relevant mutations. Herein, a novel preclinical pan KRAS (ON) inhibitor, demonstrating picomolar cellular activity across a panel of prevalent KRAS mutations is highlighted. This lead series exemplar has a differentiated mechanism of action compared to the tri complex multi RAS inhibitors currently in development, with selectivity over HRAS and NRAS. In vivo characterization to be presented includes pharmacokinetics, pharmacodynamics measuring inhibition of pERK, and efficacy in KRAS mutant tumor bearing mouse models. Citation Format: Keith Koch, Kim Alley, Karyn Bouhana, Richard Brizendine, Paul Carlson, Mark Chicarelli, Michelle Crow, Brad Fell, Jennifer Fulton, Anna Guarnieri, Jackie Harrison, John Fischer, Ravi Jalluri, Amber Johnson, Cori Malinky, Macedonio J. Mejia, Brad Newhouse, Scott Niman, Rob Rieger, John Robinson, Mareli Rodriguez, Leah Salituro, Vinny Scarato, Aaron Smith, Francis Sullivan, Yang Wang, Shannon Winski, Silas Wodd, Yeyun Zhou. Identification of a potent KRAS (ON) inhibitor with selectivity for mutant KRAS over HRAS and NRAS [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 6974.