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Discovery of 1,6-Naphthyridin-2(1H)-one Derivatives as Novel, Potent, and Selective FGFR4 Inhibitors for the Treatment of Hepatocellular Carcinoma
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-05-29 , DOI: 10.1021/acs.jmedchem.1c01977 Xiaomeng Zhang 1, 2 , Yazhou Wang 2 , Jianfeng Ji 2 , Dongjuan Si 1 , Xueting Bao 1 , Zhuangzhuang Yu 2 , Yueyue Zhu 1 , Liwen Zhao 2 , Wei Li 1 , Jian Liu 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-05-29 , DOI: 10.1021/acs.jmedchem.1c01977 Xiaomeng Zhang 1, 2 , Yazhou Wang 2 , Jianfeng Ji 2 , Dongjuan Si 1 , Xueting Bao 1 , Zhuangzhuang Yu 2 , Yueyue Zhu 1 , Liwen Zhao 2 , Wei Li 1 , Jian Liu 1
Affiliation
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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.
中文翻译：
发现 1,6-Naphthyridin-2(1H)-one 衍生物作为治疗肝细胞癌的新型、有效和选择性 FGFR4 抑制剂
成纤维细胞生长因子受体 4 (FGFR4) 已被确定为潜在的靶点，因为它传输对肝细胞癌 (HCC) 至关重要的 FGF19 信号通路。因此，针对 FGFR4 亚型的特异性 Cys552，我们设计并合成了一个新的 1,6-naphthyridin-2(1 H )-one 衍生物家族，作为有效且高选择性的 FGFR4 抑制剂。通过详细的结构优化，代表性化合物A34表现出改善的FGFR4抑制能力和选择性，以及对FGFR4依赖性HCC细胞系的优异抗增殖活性。此外，A34在 Hep-3B HCC 异种移植模型中显示出显着的抗肿瘤功效，具有良好的药代动力学特性和低 hERG 毒性风险。A34在体外还显示出对 FGFR4 V550L 突变体的中度抑制活性，这表明它具有作为 HCC 的新型抗癌剂的潜力。
更新日期：2022-05-29
中文翻译：
发现 1,6-Naphthyridin-2(1H)-one 衍生物作为治疗肝细胞癌的新型、有效和选择性 FGFR4 抑制剂
成纤维细胞生长因子受体 4 (FGFR4) 已被确定为潜在的靶点，因为它传输对肝细胞癌 (HCC) 至关重要的 FGF19 信号通路。因此，针对 FGFR4 亚型的特异性 Cys552，我们设计并合成了一个新的 1,6-naphthyridin-2(1 H )-one 衍生物家族，作为有效且高选择性的 FGFR4 抑制剂。通过详细的结构优化，代表性化合物A34表现出改善的FGFR4抑制能力和选择性，以及对FGFR4依赖性HCC细胞系的优异抗增殖活性。此外，A34在 Hep-3B HCC 异种移植模型中显示出显着的抗肿瘤功效，具有良好的药代动力学特性和低 hERG 毒性风险。A34在体外还显示出对 FGFR4 V550L 突变体的中度抑制活性，这表明它具有作为 HCC 的新型抗癌剂的潜力。
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