Abstract 3020: A novel, highly selective and potent FGFR4 inhibitor HJ-217 for the treatment of liver cancer

Abstract Background: Hepatocellular Carcinoma (HCC) is a very aggressive malignant cancer characterized by high incidence and mortality rates, which signs it continues to be a challenge for today's therapeutics. Aberrant FGF19-FGFR4 signaling occurs in approximately 30% of HCC patients and drives tumorigenesis and progression. Therefore, selectively targeting and inhibiting FGFR4 is a promisingly effective and safe therapeutic approach. Methods and Results: Here, we report a novel, highly active, and selective oral small molecule FGFR4 inhibitor HJ-217. HJ-217 exhibited significant inhibitory activity against FGFR4 kinase with the IC50 less than 1nM and showed high selectivity over FGFR1-3 subtypes as well as over 400 other kinases (with all IC50 greater than 1000 nM). HJ-217 demonstrated remarkable inhibition on cell proliferation in Hep3B liver cancer cell line and antitumor efficacy in Hep3B subcutaneous xenograft mouse model (CDX). HJ-217 has exhibited good therapeutic efficacy and low side effects in HCC treatment in clinical study. Conclusions: Our study indicates that HJ-217 is a highly selective FGFR4 inhibitor with encouraging antitumor activity, which may provide an effective treatment for HCC patients. Citation Format: Fengtian Du, Xiangyu Yang, Longjun Yang, Huiqiao Ling, Na Guo, Lina Zhang, Li Tao. A novel, highly selective and potent FGFR4 inhibitor HJ-217 for the treatment of liver cancer [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 3020.