Fibroblast growth factor receptor 4 (FGFR4) (FGFR4)

Fibroblast growth factor receptor 4 (FGFR4) is a member of the receptor tyrosine kinase family that plays a specialized role in metabolic regulation and cellular signaling [1, 2]. Unlike other FGFRs, FGFR4 is primarily expressed in the liver, where it forms a functional complex with the obligate co-receptor Klotho-beta (KLB) to bind the hormone-like ligand FGF19 [9, 15]. This signaling axis is a critical regulator of bile acid homeostasis, acting to suppress the expression of CYP7A1, the rate-limiting enzyme in the conversion of cholesterol to bile acids [13, 14]. Beyond its metabolic functions, aberrant activation of the FGF19-FGFR4 pathway is a recognized oncogenic driver in several malignancies, most notably a subset of hepatocellular carcinomas (HCC) characterized by FGF19 amplification [6, 7, 17]. Therapeutic strategies focus on the development of selective small-molecule inhibitors that often target a unique cysteine residue (Cys552) in the FGFR4 kinase domain to achieve isoform selectivity and avoid the hyperphosphatemia associated with pan-FGFR inhibition [7, 10]. However, inhibiting FGFR4 can lead to significant gastrointestinal side effects, such as diarrhea, resulting from the disruption of the bile acid feedback loop [9, 16].

Other names

CD334JTK2TKFHydroxyaryl-protein kinaseTyrosine kinase receptor

Inhibition of the intracellular tyrosine kinase domain of FGFR4, often through covalent binding to the unique Cys552 residue in the hinge region, to block downstream MAPK/ERK and PI3K/AKT signaling pathways.