Abstract 1968: Discovery of a highly potent and selective FGFR2 inhibitor for FGFR2-driven cancers

Abstract Fibroblast growth factor receptor 2 (FGFR2) is a clinically validated target and frequently altered in many solid tumors. The resulting oncogenic driver alterations often drive multiple solid tumors. Therefore, targeting FGFR2 has broad therapeutic potential. Currently, only pan-FGFR inhibitors are approved for FGFR2-driven intrahepatic cholangiocarcinoma, but not for other FGFR2-driven cancers. Due to the severe on-target toxicity associated with inhibition of FGFR1 and FGFR4, the use of the pan-FGFR inhibitors has been very limited. Thus, developing a selective FGFR2 inhibitor addresses the unmet medical need as the treatment options for FGFR2-altered cancers remain limited. Here we report the discovery and characterization of a highly selective FGFR2 inhibitor, ACE-16229210. This molecule potently inhibits FGFR2 (IC50 = 6. 2 nM) and exhibits excellent selectivity (133-fold) over other FGFR1 and FGFR4 in biochemical assays. It also potently (IC50 1 nM) and selectively (≥500-fold) inhibits FGFR2-induced ERK phosphorylation in multiple cancer cell lines harboring FGFR2 fusions, amplification, and mutations, but not those harboring FGFR1, FGFR3, or FGFR4 genetic alterations (IC50 460 nM). Furthermore, this molecule, when evaluated in a panel of 24 cell lines, demonstrates potent anti-proliferative activity against the cell lines harboring FGFR2, but not FGFR3, and especially FGFR1, or FGFR4 genetic alterations. Thus, ACE-16229210 is a potent and selective FGFR2 inhibitor. Interestingly, it exhibits the most potent activity against gatekeeper and molecular brake mutations followed by fusions, amplification, and activation loop mutations. This molecule shows a robust broad spectrum of antitumor activity with significant tumor regression at low doses (1-10 mg/kg) in several tumor xenograft and PDX models representing the major FGFR2 relevant tumor histologies including gastric, breast, ovarian, and endometrial cancers harboring clinically important FGFR2 driver alterations with a well-defined pharmacokinetic/pharmacodynamic relationship. This molecule also demonstrates strong synergistic effects when combined with irinotecan and fulvestrant in a gastric tumor model and a breast cancer PDX model harboring FGFR2 amplification, respectively. Finally, ACE-16229210 did not significantly affect serum phosphorus levels in animals at the exposure levels that are 100-fold higher than the efficacious AUC, further confirming its excellent selectivity over FGFR1. Taken together, these in vitro and in vivo studies show that ACE-16229210 is a potent and selective FGFR2 inhibitor with the potential to be developed into a more effective treatment option for multiple cancers harboring FGFR2 oncogenic driver alterations. Citation Format: Wenqian Li, Bin Liu, Junmei Wang, Tinggui Yin, Kuo-Long Yu, Sanjeev Kumar, Zhiming Wen, Genshi Zhao, Weitao Pan. Discovery of a highly potent and selective FGFR2 inhibitor for FGFR2-driven cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1968.