Structure–activity relationship studies of Imidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidine derivatives to develop selective FGFR inhibitors as anticancer agents for FGF19-overexpressed hepatocellular carcinoma

• Published in: European journal of medicinal chemistry 2025-01, Vol.282, p.117047, Article 117047
• Main Authors: Kim, Jisook, Jung, Seung Hyun, Lee, Joo Chan, Kim, Won Jeoung, Byun, Jooyun, Ahn, Young Gil, Park, Hyun-Ju
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fibroblast growth factor receptor (FGFR); Fibroblast Growth Factors - antagonists & inhibitors; Fibroblast Growth Factors - metabolism; Hepatocellular carcinoma (HCC); Humans; Imidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidine; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Male; Mice; Mice, Nude; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Receptors, Fibroblast Growth Factor - antagonists & inhibitors; Receptors, Fibroblast Growth Factor - metabolism; Structure-Activity Relationship
• ISSN: 0223-5234; 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). [Display omitted] •A series of FGFR inhibitors containing imidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidine core as a hinge-binder were synthesized.•A novel FGFR1-4 inhibitor 7n inhibited the growth of FGF19-expressing hepatocellular carcinoma cells (GI50 = 4.4∼45 nM).•7n exhibited a favorable pharmacokinetic profile and oral antitumor efficacy in human liver cancer xenograft mouse models.