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 antiproliferative potency of 0.1397 μM 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.

FGF/FGFR 通路的异常信号在癌症中经常发生，并且是许多实体瘤，尤其是肝癌的致癌驱动因素。随着对不可逆抑制剂的兴趣的重新抬头，人们已经致力于发现不可逆的 FGFR4 抑制剂。目前，设计并合成了几种含有吡咯并[2,3 - b ]吡啶-3-one和吡咯并[2,3 - d ]嘧啶-2-胺骨架的选择性不可逆抑制剂作为FGFR4抑制剂。在筛选的化合物中，衍生物25对 Hep3B 细胞系显示出优异的酶抑制活性 (IC ₅₀，51.6 nM) 和 0.1397 μM 的抗增殖效力。化合物25表现出良好的体外人肝微粒体稳定性，半衰期为 62.0 分钟，比BLU9931（46.7 分钟）更稳定。但体内药代动力学结果表明，口服生物利用度仅为6.65%，需要在下一步工作中进行改进。这些结果表明，化合物25可能是进一步研究治疗肝细胞癌的有效先导化合物。