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J Med Chem ; 67(10): 8445-8459, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38706130

ABSTRACT

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is responsible for 90% of cases. Approximately 30% of patients diagnosed with HCC are identified as displaying an aberrant expression of fibroblast growth factor 19 (FGF19)-fibroblast growth factor receptor 4 (FGFR4) as an oncogenic-driver pathway. Therefore, the control of the FGF19-FGFR4 signaling pathway with selective FGFR4 inhibitors can be a promising therapy for the treatment of HCC. We herein disclose the design and synthesis of novel FGFR4 inhibitors containing a 2,6-naphthyridine scaffold. Compound 11 displayed a nanomolar potency against Huh7 cell lines and high selectivity over FGFR1-3 that were comparable to that of fisogatinib (8) as a reference standard. Additionally, compound 11 demonstrated remarkable antitumor efficacy in the Huh7 and Hep3B HCC xenograft mouse model. Moreover, bioluminescence imaging experiments with the orthotopic mouse model support that compound 11 can be considered a promising candidate for treating HCC.


Subject(s)
Antineoplastic Agents , Carcinoma, Hepatocellular , Liver Neoplasms , Naphthyridines , Receptor, Fibroblast Growth Factor, Type 4 , Receptor, Fibroblast Growth Factor, Type 4/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 4/metabolism , Humans , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Mice , Naphthyridines/pharmacology , Naphthyridines/chemical synthesis , Naphthyridines/chemistry , Naphthyridines/therapeutic use , Cell Line, Tumor , Structure-Activity Relationship , Xenograft Model Antitumor Assays , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Cell Proliferation/drug effects , Drug Discovery , Mice, Nude , Drug Screening Assays, Antitumor
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