Abstract 4389: HJ-093, a novel, orally bioavailable, and potent pan-RAS inhibitor, for the treatment of various RAS mutation-driven cancers

Background: RAS mutations dominate tumorigenesis as they account for approximately 30% of human cancer cases, and are common in various solid tumor types such as pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal cancer (CRC). Nowadays, in the field of RAS mutated tumors treatment, only KRASG12C selective inhibitors have been approved, nonetheless, patients are prone to acquire resistance to those inhibitors. Yet there is still a lack of innovative treatments for cancers harboring other RAS mutation subtypes. Methods and Results: Here, we report a novel, orally bioavailable, and potent pan-RAS inhibitor HJ-093, for the treatment of different subsets of RAS mutations. HJ-093 exhibited significant anti-proliferative activity across various RAS mutated 3D cancer cell models including SW480, HCT116, NCI-H358, and AsPC-1, with IC50 <2 nM. In multiple RAS mutated xenograft mouse models, HJ-093 showed significant antitumor activity. HJ-093 significantly suppressed tumor growth in CT26 CRC syngeneic model either alone or in combination with anti-PD-1 antibody. Tumor regression was achieved when combined with PD-1 blockade. Conclusions: HJ-093 is a potent pan-RAS inhibitor with the potential to be developed as a targeted therapy for various RAS mutation-driven cancers. Citation Format: Fengtian Du, Xiangyu Yang, Shuai Luo, Jingyu Tian, Li Zhang, Huiqiao Ling, Na Guo, Ruisi Wu, Qingqing Qian, Li Tao. HJ-093, a novel, orally bioavailable, and potent pan-RAS inhibitor, for the treatment of various RAS mutation-driven 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 4389.