Abstract LB431: Discovery and characterization of a highly potent and orally available small-molecule inhibitor for diverse KRAS mutations

Abstract KRAS is frequently mutated in human cancers, including pancreatic (∼90%), colorectal (∼35%), and lung cancers (∼25%). While selective inhibitors targeting KRASG12C and KRASG12D mutations have been identified and are either approved or in clinical development, there remains a significant unmet need for therapies targeting other highly prevalent KRAS mutations, such as KRASG12V. This study describes the discovery and preclinical characterization of ABK-KRAS-1, a novel, potent, and highly orally bioavailable small-molecule inhibitor with broad activities against multiple KRAS mutations. ABK-KRAS-1 exhibited high binding affinity and strong biochemical activity against a range of KRAS mutations in vitro. In cellular experiments, treatment with ABK-KRAS-1 effectively inhibited KRAS signaling across a diverse panel of KRAS mutant cancer cell lines, demonstrated by reduced phosphorylation of ERK1/2 (p-ERK). Additionally, ABK-KRAS-1 significantly impaired cell viability at sub-nanomolar to nanomolar concentrations. In vivo efficacy studies further demonstrated robust anti-tumor activity of ABK-KRAS-1 in multiple xenograft models dependent on various KRAS mutations. Preclinical DMPK analyses confirmed excellent bioavailability across multiple animal species. Collectively, the superior preclinical profile of ABK-KRAS-1 supports its advancement into preclinical development. Citation Format: Yongxian Zhang, Fei Yang, Zhigang Feng, Meimei Sun, Xinyan Huang, Haibing Deng, Hongping Yu, Yao-chang Xu, Zhui Chen, Haiyan Ying. Discovery and characterization of a highly potent and orally available small-molecule inhibitor for diverse KRAS mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB431.