Abstract 4383: Discovery of ID12241161, an oral KRASmulti inhibitor demonstrating potent and selective anti-cancer effects in KRAS-dependent cancers

Abstract Kirsten rat sarcoma virus (KRAS) gene mutations are prevalent in multiple cancers, contributing to approximately 89%, 44%, and 30% of pancreatic, colorectal, and lung adenocarcinomas, respectively. These mutations are associated with poor prognosis, and limited treatment options for all KRAS mutations, except for G12C, highlights the urgent need for oncogene targeted therapies. Despite ongoing development of KRAS pathway-targeting drugs, balancing safety and efficacy remains challenge owing to its essential role in cellular functions across various tissues. Through extensive computational analysis and structure-based drug design, we developed ID12241161, a novel, potent, and orally available small molecule inhibitor that favorably positions within the KRAS switch II pocket to target both “ON” and “OFF” states of diverse KRAS mutants. In this study, we demonstrated that ID12241161 exhibited robust anti-proliferative effects in vitro at picomolar to nanomolar concentrations (most IC50 values were lower than 10 nM) across a range of cancer cell lines with KRAS mutations or amplifications. Significant pharmacodynamic modulation of biomarkers was observed, including the inhibition of ERK1/2 phosphorylation, in these KRAS-dependent cell lines. In KRAS-independent cells, minimal cytotoxicity was observed, even at micromolar concentrations, suggesting that ID12241161 selectively targets KRAS-driven cancers. In mice, the pharmacokinetic profile of ID12241161 is characterized by a half-life of 6 hours with a high volume of distribution, which allows sustained effects for over 24 hours following once-daily dosing. Furthermore, in vivo studies demonstrated that a daily oral dose of 5-15 mg/kg ID12241161 was well tolerated and effectively induces tumor regression in KRAS-dependent xenograft models representing various cancer types. Our data indicated that ID12241161 possesses potent anticancer effects in KRAS-dependent cancers, with a wide safety margin and favorable pharmacokinetics, allowing for once-daily dosing. These findings support the potential use of ID12241161 as a viable treatment option for patients with KRAS-driven cancers. Citation Format: Jeong Eun Kim, Sung Hoon Lee, Jong-Hwa Lee, Changhee Hong, Yoonsung Song, Dowon Kim, Won Sik Lee, Myongjae Lee. Discovery of ID12241161, an oral KRASmulti inhibitor demonstrating potent and selective anti-cancer effects in KRAS-dependent cancers [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 4383.