6-Amino-2,4,5-trimethylpyridin-3-ol and 2-amino-4,6-dimethylpyrimidin-5-ol derivatives as selective fibroblast growth factor receptor 4 inhibitors: design, synthesis, molecular docking, and anti-hepatocellular carcinoma efficacy evaluation

A novel series of aminotrimethylpyridinol and aminodimethylpyrimidinol derivatives were designed and synthesised for FGFR4 inhibitors. Structure-activity relationship on the FGFR4 inhibitory activity of the new compounds was dearly elucidated by an intensive molecular docking study. Anti-cancer activity of the compounds was evaluated using hepatocellular carcinoma (HCC) cell lines and a chick chorioallantoic membrane (CAM) tumour model. Compound 60 showed FGFR4 inhibitory activity over FGFR1 3. Compared to the positive control BLU9931, compound 60 exhibited at least 8 times higher FGFR4 selectivity. Strong antiproliferative activity of compound 60 was observed against Hep3B, an HCC cell line which was a much more sensitive cell line to BLU9931. In vivo anti-tumour activity of compound 60 against Hep3B-xenografted CAM tumour model was almost similar to BLU9931. Overall, compound 60, a novel derivative of aminodimethyl-pyrimidinol, was a selective FGFR4 kinase inhibitor blocking HCC tumour growth. [GRAPHICS] .

Automated summary

A series of novel compounds were designed and synthesized as FGFR4 inhibitors. Their inhibitory activity on FGFR4 was elucidated through molecular docking and their anti-cancer activity was evaluated in cell lines and animal models. Compound 60 showed high selectivity and strong anti-proliferative activity against Hep3B, indicating its potential therapeutic effect on hepatocellular carcinoma.