成纤维细胞生长因子受体4
FGF19型
肝细胞癌
化学
癌症研究
成纤维细胞生长因子受体1
癌症
成纤维细胞生长因子
受体
成纤维细胞生长因子受体
内科学
生物化学
医学
作者
Hyun-Jeong Oh,Jisook Kim,Seung Hyun Jung,Tae Yong Ha,Young Gil Ahn,Gibeom Nam,Kyeongwon Moon,Pardeep Singh,In Su Kim
标识
DOI:10.1021/acs.jmedchem.4c00758
摘要
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.
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