Design, Synthesis, and Biological Evaluation of 2‑Formyl Tetrahydronaphthyridine Urea Derivatives as New Selective Covalently Reversible FGFR4 Inhibitors

Aberrant
FGF19/FGFR4 signaling is an oncogenic driver force for
the development of human hepatocellular carcinoma (HCC). A series
of 2-formyl tetrahydronaphthyridine urea derivatives were designed
and synthesized as new covalently reversible inhibitors of FGFR4.
The representative compound 9ka exhibited an IC50 value of 5.4 nM against FGFR4 and demonstrated extraordinary kinome
selectivity. Compound 9ka also exhibited good oral pharmacokinetic
properties with an AUC(0‑t) value of 38 950.06
h·ng/mL, a T1/2 value of 3.06 h,
and an oral bioavailability of 50.97%, at an oral dose of 25 mg/kg
in Sprague-Dawley (SD) rats. Furthermore, compound 9ka induced significant tumor regressions in a xenograft mouse model
of Hep3B2.1-7 HCC cell line without an obvious sign of toxicity upon
30 mg/kg oral administration. Compound 9ka may serve
as a promising lead compound for further anticancer drug development.