Advancements in Targeted Therapy: The Development of a Selective FGFR4 Inhibitor for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a significant cause of cancer-related mortality globally, with an increasing incidence rate. A subset of HCC cases, estimated at 10-30%, exhibit abnormal FGF19-FGFR4 signaling, contributing to tumor growth. The use of broad-spectrum FGFR inhibitors in clinical settings often leads to hyperphosphatemia due to the impact on FGFR1. This has prompted the search for a more targeted therapy, focusing on FGFR4, to potentially enhance safety and efficacy.

A new compound, ABSK-011, has been developed through computational structural analysis and medicinal chemistry. It is a small molecule that selectively inhibits FGFR4 and has shown significant anti-tumor effects in HCC model systems. The compound has been tested for its inhibitory effects on FGFR4 enzymatic and cellular activities using biochemical assays and has demonstrated high selectivity against other FGFR family members through various profiling techniques.

Pharmacokinetic studies of ABSK-011 have been conducted in multiple animal species, and its efficacy has been evaluated in two HCC xenograft models. The compound has shown to irreversibly bind to a specific residue in FGFR4, leading to its high selectivity and potency, with an IC50 value less than 10 nM. It also exhibits a significant selectivity advantage over other receptor tyrosine kinases.

In vivo studies have revealed that ABSK-011 has a favorable pharmacokinetic profile and effectively inhibits tumor growth in a dose-dependent manner. The compound's impact on tumor growth correlates well with the inhibition of FGFR4 signaling. Preliminary safety assessments indicate that ABSK-011 does not affect CYP family members or hERG channels.

Abbisko Therapeutics has presented ABSK-011 as a potent and selective FGFR4 inhibitor suitable for oral administration. Its comprehensive profile suggests that it is a promising candidate for accelerated preclinical development. The findings were presented at the American Association for Cancer Research Annual Meeting in 2018.