Design, synthesis, and biological evaluation of Ponatinib-based N-Phenylpyrimidine-2-amine derivatives as novel fibroblast growth factor receptor 4 (FGFR4) selective inhibitors.

Fibroblast growth factor receptor 4 (FGFR4) has been proven to be a promising target for FGFR-driven HCC therapy. Great efforts have been devoted to the discovery of FGFR4 inhibitors. In this article, a new class of Ponatinib-based N-phenylpyridine-2-amine derivatives was designed and synthesized as covalent and irreversible FGFR4 selective inhibitors through a rational drug design strategy. The representative compound 10f displayed significant FGFR4 inhibition and reasonable selectivity. Meanwhile, compound 10f strongly suppressed the proliferation of FGFR4 dependent HCC cells both in vitro and in vivo by inhibiting the FGFR4 signaling pathway. Moreover, the irreversible binding to Cys552 in FGFR4 of compound 10f was also characterized by LC-MS/MS. These results provide evidence of 10f as a potential lead compound targeting FGFR4 for anti-HCC agent development.