Abstract LB-272: Discovery and characterization of a novel FGFR4 Inhibitor for the treatment of hepatocellular carcinoma
Authors: Chen Zhui 
Published: August 2018

Introduction: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and has one of the fastest growing incidence among cancers. Aberrant FGF19-FGFR4 signaling occurs in 10-30% of HCC patients and drives tumor development and progression. Pan-FGFR inhibitors are associated with hyperphosphatemia in clinic due to inhibition of FGFR1. Therefore, selectively targeting FGFR4 may render a safer treatment approach with improved clinical benefits. Using advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a novel and highly selective small molecular FGFR4 inhibitor, ABSK-011, demonstrating robust anti-tumor activity in hepatocellular carcinoma models.

Method: ABSK-011 was evaluated in biochemical Caliper assay and Celltiter-Glo assay for its inhibition on FGFR4 enzymatic and cellular activities. Its selectivity against other FGFR family members was analyzed through related biochemical, cellular, and KinomeScan profiling assays. The pharmacokinetics (PK) profile of ABSK-011 was characterized across various species of animals including mouse, rat and dog. Efficacy studies were conducted in two HCC xenograft models, and preliminary toxicity profile was also evaluated.

Results: ABSK-011 inhibits FGFR4 with IC50 &lt; 10 nM in biochemical assay and exhibits at least 50 fold selectivity against other FGFR kinases. The strong selectivity arises from the ability of ABSK-011 to irreversibly modify Cys552, a residue within the active site of FGFR4 that is not conserved among other FGFR kinases. ABSK-011 also shows greater than 800-fold selectivity against other RTK members. In HCC cells with autocrine production of FGF19, ABSK-011 inhibits the auto-phosphorylation of FGFR4 and blocks signal transduction from FGFR4 to downstream pathway activation. HCC cell lines harboring amplification and overexpression of FGF19 are uniquely sensitive to growth inhibition by ABSK-011 (EC50 &lt; 50 nM) compared with cancer cell lines with FGFR1 dependence (EC50 &gt; 2000 nM), confirming selectivity for FGFR4 over FGFR1.

In vivo PK study demonstrated high exposure and superior DMPK profile of ABSK-011 in mouse, rat and dog. In preclinical in vivo studies, oral administration of ABSK-011 strongly inhibits the growth and induces regressions of subcutaneous xenograft tumors dependent upon FGFR4 activity. Suppression of tumor growth is dose dependent and well correlated with pharmacodynamic inhibition of FGFR4 signaling. Safety studies showed that ABSK-011 has no inhibition on CYP family members, hERG, etc.

Conclusion: ABSK-011, presented here by Abbisko Therapeutics, is a highly potent, selective, and oral-available small molecular FGFR4 inhibitor. Its superior profile supports fast-track preclinical development.

Citation Format: Zhui Chen. Discovery and characterization of a novel FGFR4 Inhibitor for the treatment of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-272.