Structure-activity relationship studies of Imidazo1',2':1,6pyrido2,3-dpyrimidine derivatives to develop selective FGFR inhibitors as anticancer agents for FGF19-overexpressed hepatocellular carcinoma

• Published in: European journal of medicinal chemistry Vol. 282; p. 117047
• Main Authors: Kim, Jisook, Jung, Seung Hyun, Lee, Joo Chan, Kim, Won Jeoung, Byun, Jooyun, Ahn, Young Gil, Park, Hyun-Ju
• Format: Journal Article
• Language: English
• Published: 12-11-2024
• ISSN: 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.117047

The aberrant activation of fibroblast growth factor (FGF) and FGF receptor (FGFR)-mediated signaling pathways are associated with cancer development, including hepatocellular carcinoma (HCC). A novel series of imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine, containing an acrylamide covalent warhead, were synthesized as selective FGFR 1-4 inhibitors. Compound 7n was identified as the most potent inhibitor against FGFR1, 2, and 4, with IC50 values of 8/4 nM (FGFR1/2) and 3.8 nM (FGFR4), and the covalent docking analyses suggested that 7n form a covalent adduct with cysteine residue on the hinge or p-loop of FGFR. Compound 7n exhibited a favorable pharmacokinetic profile and significant in vivo antitumor efficacy in human liver cancer xenograft mouse models (xenograft, FGF/FGFR-dependent HCC cells).The aberrant activation of fibroblast growth factor (FGF) and FGF receptor (FGFR)-mediated signaling pathways are associated with cancer development, including hepatocellular carcinoma (HCC). A novel series of imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine, containing an acrylamide covalent warhead, were synthesized as selective FGFR 1-4 inhibitors. Compound 7n was identified as the most potent inhibitor against FGFR1, 2, and 4, with IC50 values of 8/4 nM (FGFR1/2) and 3.8 nM (FGFR4), and the covalent docking analyses suggested that 7n form a covalent adduct with cysteine residue on the hinge or p-loop of FGFR. Compound 7n exhibited a favorable pharmacokinetic profile and significant in vivo antitumor efficacy in human liver cancer xenograft mouse models (xenograft, FGF/FGFR-dependent HCC cells).