Discovery of novel FGFR4 inhibitors through a build-up fragment strategy

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. FGFR4 has been implicated in HCC progression, making it a promising therapeutic target. We introduce an approach for identifying novel FGFR4 inhibitors by sequentially adding fragments to a common warhead unit. This strategy resulted in the discovery of a potent inhibitor, 4c, with an IC₅₀ of 33 nM and high selectivity among members of the FGFR family. Although further optimisation is required, our approach demonstrated the potential for discovering potent FGFR4 inhibitors for HCC treatment, and provides a useful method for obtaining hit compounds from small fragments.

Keywords:

• FGFR4
• small molecule
• hit identification
• kinase inhibitor
• fragment

Authors contributions

J.K. mainly conducted the experimental work with support from C.G.I., K.O., J.M.L., and F.A.R. in the preparation of some derivatives, as well as in the data collection and interpretation. K.H.M. conceptualised and designed the experiment, and prepared the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The data supporting the findings of this study are available within the article.

Additional information

Funding

This research was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korean Government [2022R1A2C2010824].