Abstract Oncogenic KRAS mutations occur across multiple cancer types, including pancreatic, lung, and colorectal malignancies. While allele-specific KRAS inhibitors have demonstrated clinical benefit in patients, the majority of KRAS mutant cancers remain without effective therapies. Recent efforts to address this disparity have resulted in the identification of pan KRAS inhibitors that target clinically relevant mutations and alterations. Herein, we highlight the clinical candidate CGT1263, a novel pan KRAS inhibitor that engages both the active (ON) and inactive (OFF) states of KRAS while sparing HRAS and NRAS inhibition. CGT1263 demonstrates robust anti-proliferative activity across a tumor spheroid panel of KRAS altered cell lines. In vivo characterization of CGT1815, the prodrug of CGT1263, includes steady state pharmacokinetics across species, pharmacodynamics, and efficacy in KRAS altered mouse tumor 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 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 Wood, Yeyun Zhou. Characterization of CGT1263, a KRAS (ON/OFF) inhibitor clinical candidate with selectivity for mutant KRAS over HRAS and NRAS abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 410.
Fischer et al. (Fri,) studied this question.