Pyrrolo[2,3-b]pyridine-3-one derivatives as novel fibroblast growth factor receptor 4 inhibitors for the treatment of hepatocellular carcinoma

Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors, especially liver cancer. With the resurgence of interest in irreversible inhibitors, efforts have been directed to the discovery of irreversible FGFR4 inhibitors. Currently, several selective irreversible inhibitors containing pyrrolo[2,3-b]pyridine-3-one and pyrrolo [2,3-d]pyrimidin-2-amine skeletons were designed and synthesized as FGFR4 inhibitors. Among the screened compounds, derivative 25 showed excellent enzymatic inhibitory activity (IC50, 51.6 nM) and antipmliferative potency of 0.1397 mu M against Hep3B cell lines. Compound 25 exhibited good in vitro human liver microsomal stability with the half-life of 62.0 min, which was more stable than BLU9931 (46.7 min). But the in vivo pharmacokinetic results showed that the oral bioavailability was only 6.65%, which needs to be improved in the next work. These results showed that compound 25 might be an effective lead compound for further investigation to treat the hepatocellular carcinoma.

Automated summary

In this study, several irreversible FGFR4 inhibitors containing pyrrolo were designed and synthesized, among which derivative 25 showed excellent antiproliferative activity against Hep3B cell lines and good in vitro human liver microsomal stability. Compound 25 might be a promising lead compound for further investigation in treating hepatocellular carcinoma, although its oral bioavailability needs improvement.