Abstract B024: Identification of a potent KRAS (ON) inhibitor clinical candidate series 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 with KRAS mutations are identified 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 designed to target clinically relevant mutations. Herein we highlight an advanced candidate series demonstrating pan KRAS (ON) inhibition with picomolar cellular activity across a panel of prevalent KRAS mutations. This compound 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: John Fischer, Kim Alley, Karyn Bouhana, Richard Brizendine, Paul Carlson, Mark Chicarelli, Michelle Crow, Brad Fell, Jennifer Fulton, Anna Guarnieri, Jackie Harrison, Ravi Jalluri, Amber Johnson, Keith Koch, Cori Malinky, Macedonio Mejia, Brad Newhouse, Scott Niman, Rob Rieger, John Robinson, Mareli Rodriguez, Leah Salituro, Vinny Scarato, Aaron Smith, Francis Sullivan, Yang Wang, Shannon Winski, Silas Wood, Yeyun Zhou. Identification of a potent KRAS (ON) inhibitor clinical candidate series with selectivity for mutant KRAS over HRAS and NRAS [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B024.