Abstract 3018: Discovery of SIGX1094R, a novel FAK inhibitor simultaneously blocking FAK and SRC signaling

Abstract Diffuse gastric cancer (DGC) is a highly lethal malignancy with only minimally effective systemic therapies. Our previous studies identified the Focal Adhesion Kinase (FAK) as a novel and promising target for DGC. To enhance the efficacy of FAK inhibition in cancer therapy, we developed a potent small-molecule inhibitor, SIGX1094R. This inhibitor targets both FAK and the related kinase SRC, which complexes with FAK, whereas current FAK inhibitors in clinical trials only inhibit p-FAK.In DGC cell line models and mouse organoid models, SIGX1094R significantly inhibited cell growth and demonstrated much greater potency than current FAK inhibitors in clinical trials, with similar results observed in DGC patient-derived organoids. To further evaluate efficacy, we found that SIGX1094R significantly blocked tumor growth in several DGC patient-derived xenografts, whereas current first-line drugs demonstrated limited efficacy. This aligns with clinical results, highlighting SIGX1094R's strong potential to replace the existing standard of care. Additionally, SIGX1094R demonstrated significantly greater efficacy in ascites models (both in vitro and in vivo) compared to the current standard treatments. In addition to treating DGC, SIGX1094R shows promise in preclinical studies for treating ovarian, triple-negative breast, and pancreatic cancers. It also has high potential for use in combination therapies with targeted treatments for KRAS and EGFR mutations. GLP tox studies demonstrated that most of the lesions in high dose of SIGX1094R animals at the end of the recovery period were fully recovered.The drug received investigational New Drug (lND) clearance both from the U.S. Food and Drug Administration (FDA) and the National Medical Products Administration (NMPA) in China. SIGX1094R, poised to be the world’s first targeted therapy for DGC, is the inaugural project in a pipeline discovered by AI and validated using organoid disease models. Citation Format: Haisheng Zhang, Shu Zhuo, Lei Zhang, Lin Li, Wanfen Peng, Fengtao Jiang, Yufang Chen, Lin Lin. Discovery of SIGX1094R, a novel FAK inhibitor simultaneously blocking FAK and SRC signaling [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 3018.