期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 11, 页码 7595-7618出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01977
关键词
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资金
- National Science Foundation of China [81703342, 81573304]
- Natural Science Foundation of Jiangsu [BK20211301]
- Natural Science Foundation of Nanjing University of Chinese Medicine [NZY81703342]
Fibroblast growth factor receptor 4 (FGFR4) has been identified as a potential target for hepatocellular carcinoma (HCC). A novel family of potent FGFR4 inhibitors, represented by compound A34, was designed and synthesized. A34 exhibited improved FGFR4 inhibitory capability and excellent anti-proliferative activities against FGFR4-dependent HCC cell lines, indicating its potential as a novel anticancer agent for HCC.
Fibroblast growth factor receptor 4 (FGFR4) has been identified as a potential target due to its transmission of the FGF19 signaling pathway, which is critical to hepatocellular carcinoma (HCC). Therefore, focusing on the specific Cys552 of FGFR4 subtype, we designed and synthesized a novel family of 1,6-naphthyridin-2(1H)-one derivatives as potent and highly selective FGFR4 inhibitors. Through detailed structural optimizations, the representative compound A34 exhibited improved FGFR4 inhibitory capability and selectivity and excellent anti-proliferative activities against FGFR4-dependent HCC cell lines. Additionally, A34 demonstrated remarkable antitumor efficacy in a Hep-3B HCC xenograft model, with favorable pharmacokinetic properties, and low risk of hERG toxicity. A34 also showed moderate inhibitory activities against the FGFR4 V550L mutant in vitro, which indicates that it has the potential as a novel anticancer agent for HCC.
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