Abstract 4369: Preclinical characterization of a dual-state pan-KRAS Inhibitor

Abstract Activating mutations in KRAS occur in greater than twenty percent of all cancers encompassing several solid tumors with significant unmet medical need, including lung, colon, pancreatic, endometrial and stomach cancers. While mutations of codon 12 of KRAS (encoding glycine) are the most common, activating missense mutations are also observed at codons 13 and 61. Guided by our experience in the successful development of the covalent KRAS G12C mutant-selective inhibitor, sotorasib, we leveraged structure-based design to identify a new class of reversible, pan-KRAS inhibitors capable of targeting an expanded set of hot spot mutations prevalent in the above tumor types (e.g., KRAS G12D, G12V, G13D and Q61H). These reversible inhibitors potently inhibit both the GDP(OFF)- and GTP(ON)-states of KRAS while sparing H/NRAS. Dual ON/OFF-state activity facilitates the inhibition of mutant alleles that rapidly cycle between ON and OFF states (e.g., KRAS G12C) as well as those demonstrating slower cycling (e.g., KRAS G12V & KRAS Q61H), which predominantly reside in the GTP-bound state. Mechanistically, these inhibitors block the interaction of KRAS with its downstream effectors, such as c-RAF, and potently inhibit ERK phosphorylation. In vivo profiling demonstrated promising preclinical efficacy in KRAS G12D and KRAS G12V xenograft models, and good tolerability, illustrating the potential of pan-KRAS inhibitors to extend therapeutic benefit to tumors beyond those with KRAS G12C mutations. Citation Format: Kevin Gaida, Tao Osgood, Ying-Chu Chen, Deanna Mohn, Anne Y. Saiki, Gilbert Diaz, Monica Leavitt, Upendra Dahal, Amit Vaish, Jason DeVoss, Karen Rex, Ryan Wurz, Brian A. Lanman, Paul E. Hughes, Rati Verma. Preclinical characterization of a dual-state pan-KRAS Inhibitor [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 4369.