Abstract 4386: HJ-099, a novel, orally bioavailable pan-KRAS (ON) non-covalent inhibitor, demonstrates significant antitumor activity in multiple preclinical models with KRAS mutations

Abstract Background: KRAS is one of the most common mutated oncogenes in cancer, which primarily stimulates tumor growth by activating the MAPK pathway. Tumors with non-KRASG12C mutations, such as KRASG12D, KRASG12V, and other codon mutation subtypes, currently lack compelling precision medicines. Therefore, the development of pan-KRAS inhibitor is an unmet and pressing clinical need. Methods and Results: Here, we report a novel, orally bioavailable pan-KRAS (ON) inhibitor HJ-099, designed to treat various KRAS mutation-driven tumors. HJ-099 exhibited significant anti-proliferative activity against multiple KRAS mutated cancer cell lines, including SW620, MAI PaCa-2, NCI-H358, AsPC-1, and NCI-H441, with IC50 <1.5 nM. In multiple KRAS mutated xenograft mouse models, HJ-099 showed significant inhibition on tumor growth. Tissue distribution study in tumor-bearing murine model showed that HJ-099, after oral administration, were mainly detected in the tumors, and the long-lasting accumulation of HJ-099 in tumor tissues resulted in more potent and durable antitumor activity in vivo. Conclusions: The study indicates that HJ-099 is a novel, highly active pan-KRAS (ON) inhibitor that shows significant tumor suppression activity against major KRAS mutation subtypes, and merits clinical evaluation. Citation Format: Xiangyu Yang, Fengtian Du, Na Guo, Huiqiao Ling, Shuai Luo, Xiaorong Yu, Qingqing Qian, Ruisi Wu, Jingyu Tian, Jianxin Ji, Li Zhang. HJ-099, a novel, orally bioavailable pan-KRAS (ON) non-covalent inhibitor, demonstrates significant antitumor activity in multiple preclinical models with KRAS mutations [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 4386.