Abstract 4390: HJ-119, a novel, highly selective, orally bioavailable small molecule KRASG12D inhibitor

Background: KRAS mutations are present in approximately 25% of human cancers, among which KRASG12D is the most common hotspot mutation subtype, accounting for 20%-50% of all KRAS mutations. KRASG12D mutation frequently occur in cancers such as pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC). Currently, no drug directly targeting KRASG12D has been approved. An effective therapy for KRASG12D mutant cancers represents a significant unmet need. Methods and Results: We developed a novel, highly selective, orally bioavailable small molecule inhibitor of KRASG12D, denoted as HJ-119, and evaluated its antitumor activities in both in vitro and in vivo studies. In vitro, HJ-119 exhibited effective antiproliferative activities against various KRASG12D mutant cell lines, including AsPC-1, A427, and GP2D, with IC50 < 15 nM. Consistent with the in vitro data, in AsPC-1 xenograft mouse model, tumor growth was significantly inhibited after HJ-119 treated and favorable safety profile was presented. Conclusions: Our findings demonstrate the potent antitumor activity of HJ-119, and manifest a promisingly therapeutic prospect for patients suffering from KRASG12D mutant tumors. Citation Format: Fengtian Du, Huiqiao Ling, Shuai Luo, Li Zhang, Ruisi Wu, Zhenlong Gao, Na Guo, Li Tao. HJ-119, a novel, highly selective, orally bioavailable small molecule KRASG12D inhibitor [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 4390.