Abstract 3013: GSC000829, a novel selective FGFR2/3 inhibitor, displays superior antitumor activity in preclinical FGFR-driven neoplasms models

Fibroblast growth factors (FGF) and their receptors (FGFRs) are pivotal in a myriad of cellular functions. Tumorigenesis onset due to FGFR genomic alterations is commonly observed across diverse solid tumors. Although several FGFR inhibitors targeting FGFR1-3 or FGFR1-4 have gained approval for treating various solid tumors, their widespread application is hindered by the development of resistant gatekeeper mutations in FGFR proteins and toxicities linked to FGFR1 and/or FGFR4, necessitating precise dosing or even drug withdrawal. Here, we report the discovery of a novel pre-clinical candidate compound GSC000829 with a strong inhibition towards FGFR2/3 and a significantly improved selectivity over FGFR1 and FGFR4. Furthermore, GSC000829 shows excellent efficacy in various biochemical and cellular assays corresponding to different FGFR fusions or mutations. It also demonstrates enhanced antitumor activity at lower dosage in FGFR3-driven CDX models compared to the pan-FGFR inhibitor Erdafitinib, as well as other FGFR3-selective inhibitors such as TYRA300 and LOXO-435. GSC000829 exhibits favorable physicochemical and pharmacokinetic properties along with an excellent preclinical toxicity profile with no obvious phosphate increase at quite high exposure level in rats. Taken together, these findings bolster the rationale for advancing GSC000829 into clinical trials as a potential best-in-class FGFR isoform-selective inhibitors, offering an approach for treating advanced solid tumors harboring FGFR2/3 aberrations. Citation Format: Tian Han, Donglin Fu, Tao Cheng, Yuanfeng Xia, Zhilong Hu, Fanglong Yang. GSC000829, a novel selective FGFR2/3 inhibitor, displays superior antitumor activity in preclinical FGFR-driven neoplasms models [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 3013.