Insight into the design of FGFR4 selective inhibitors in cancer therapy: Prospects and challenges

Recently, FGFR4 has become a hot target for the treatment of cancer owing to its important role in cellular physiological processes. FGFR4 has been validated to be closely related to the occurrence of cancers, such as hepatocellular carcinoma, rhabdomyosarcoma, breast cancer and colorectal cancer. Hence, the development of FGFR4 small-molecule inhibitors is essential to further understanding the functions of FGFR4 in cancer and the treatment of FGFR4-dependent diseases. Given the particular structures of FGFR1-4, the development of FGFR4 selective inhibitors presents significant challenges. The non-conserved Cys552 in the hinge region of the FGFR4 complex becomes the key to the selectivity of FGFR4 and FGFR1/2/3 inhibitors. In this review, we systematically introduce the close relationship between FGFR4 and cancer, and conduct an in-depth analysis of the developing methodology, binding mechanism, kinase selectivity, pharmacokinetic characteristics of FGFR4 selectivity inhibitors, and their application in clinical research.