LAUSR

Introduction: Aberrant activation of FGF19-FGFR4 signaling pathway plays an essential role in the tumorigenesis of Hepatocellular carcinoma (HCC) and FGFR4 inhibitors have shown preliminary efficacy in recent clinical trials for patients with FGF19 overexpression. However, the observed responses only lasted a few months before tumors relapse. Acquired FGFR4 resistant mutations were found in ~30% of FGFR4 inhibitor responsive patients. Similar FGFR4 mutations haven also been found de novo in about 7-10% of Rhabdomyosarcoma (RMS) and ER-treated invasive lobular carcinoma patients. First generation FGFR4 inhibitors have minimal activity against these de novo or acquired resistant mutations. Therefore, next-generation of FGFR4 inhibitors are needed to overcome these resistant FGFR4 mutations to provide better treatment options for patients. Using advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a next-generation small molecule FGFR4 inhibitor, ABSK012, and demonstrated its strong activities against de novo and acquired resistant FGFR4 mutations while retaining inhibition for wild-type FGFR4. Method: Inhibitory activity of ABSK012 against FGFR4 and FGFR4 mutants was evaluated by MSA assay and its inhibition on FGFR4-dependent cell proliferation was evaluated by Celltiter-Glo assay in wile type FGFR4-dependent cancer cell lines or mutant FGFR4-dependent Ba/f3 cell lines. Its selectivity against other FGFR family member and kinases was analyzed by cellular and KinomeScan profiling. Efficacy studies were conducted in HCC xenograft models and mutant FGFR4-dependent xenograft models including a RMS PDX model harboring FGFR4 V550L mutation. Results: ABSK012 demonstrated strong potency over multiple FGFR4 mutants that are insensitive to a first generation FGFR4 inhibitor BLU-554. It also inhibited wild-type FGFR4 with IC50<5 nM in biochemical assay and exhibited great selectivity against other kinases. In multiple mutant and wild-type FGFR4-dependent cell lines, ABSK012 demonstrated significantly improved anti-proliferation activity. In preclinical in vivo studies in HCC models, oral administration of ABSK012 strongly inhibited the tumor growth at doses without obvious toxicities. More importantly, in a RMS PDX xenograft harboring FGFR4 V550L mutation, ABSK012 also showed significant anti-tumor activity. Other ADME and safety profiling demonstrated excellent drug-like properties of ABSK012. Conclusion: ABSK012, presented here by Abbisko Therapeutics, is a highly potent, selective, and next-generation small molecule FGFR4 inhibitor overcoming FGFR4 mutations resistant to first-generation inhibitors. Its superior preclinical profile supports its fast-track development into clinic. Citation Format: Haiyan Ying, Nannan Zhang, Haibing Deng, Fei Yang, Wenqun Xin, Bin Shen, Hongping Yu, Zhui Chen, Yao-chang Xu. Discovery & characterization of a next-generation FGFR4 inhibitor overcoming resistant mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB328.