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 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.
['Jin|Qiaomei|Q|', 'Zhang|Dongjian|D|', 'Gao|Meng|M|', 'Jiang|Cuihua|C|', 'Zhang|Jian|J|']
D000284:Administration, Oral D000818:Animals D000970:Antineoplastic Agents D006528:Carcinoma, Hepatocellular D045744:Cell Line, Tumor D049109:Cell Proliferation D004305:Dose-Response Relationship, Drug D004354:Drug Screening Assays, Antitumor D006801:Humans D007275:Injections, Intravenous D008113:Liver Neoplasms D008297:Male D008862:Microsomes, Liver D062105:Molecular Docking Simulation D015394:Molecular Structure D047428:Protein Kinase Inhibitors D011725:Pyridines D051381:Rats D017207:Rats, Sprague-Dawley D051499:Receptor, Fibroblast Growth Factor, Type 4 D013329:Structure-Activity Relationship
Pyrrolo[2,3-b]pyridine-3-one derivatives Hepatocellular carcinoma FGFR4 inhibitors Reversible-covalent