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

Abstract

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 clearly 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 6O showed FGFR4 inhibitory activity over FGFR1 − 3. Compared to the positive control BLU9931, compound 6O exhibited at least 8 times higher FGFR4 selectivity. Strong anti-proliferative activity of compound 6O 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 6O against Hep3B-xenografted CAM tumour model was almost similar to BLU9931. Overall, compound 6O, a novel derivative of aminodimethylpyrimidinol, was a selective FGFR4 kinase inhibitor blocking HCC tumour growth.

Graphical abstract

Highlights

• A series of methylated aminopyri(mi)dine compounds were designed and synthesised as FGFR4 inhibitors.

• Compound 6O showed a selective FGFR4 inhibitory activity over FGFR1 ∼ 3.

• Dimethyl groups at the pyrimidine ring of compound 6O prohibited a proper conformation for covalent bonding to FGFR1 ∼ 3.

• The smaller size of fluorine at the dimethoxyphenyl ring in compound 6O gives suitable conformation for strong binding interaction with FGFR4.

• Compound 6O inhibited Hep3B tumour growth xenografted on chick chorioallantoic membrane (CAM) tumour model

Keywords:

• Aminotrimethylpyri(mi)dinol
• FGFR4 kinase
• molecular docking
• hepatocellular carcinoma
• anti-tumour

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the National Research Foundation of Korea (NRF) funded by the Korean Ministry of Science and ICT (MSIT) [Grant No. NRF-2018R1A2B6001299 and NRF-2020R1A2C2005690].