Structure-based design, synthesis, and evaluation of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives as novel c-Met inhibitors
Structure-based design, synthesis, and evaluation of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives as novel c-Met inhibitors
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基于结构的设计、合成和评估 4,5,6,7-四氢-1H-吡唑并[4,3-c]吡啶衍生物作为新型 c-Met 抑制剂
DOI：
10.1016/j.ejmech.2017.06.057
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发表时间：
2017
影响因子：
6.7
通讯作者：
Chen Yadong
中科院分区：
文献类型：
--
作者：
Zhang Li;Zhang Beichen;Zhao Jingyun;Zhi Yanle;Wang Lu;Lu Tao;Chen Yadong
c-Met 正在成为癌症靶向治疗的一个有吸引力的靶标，因为在多种肿瘤类型中都观察到了 c-Met 的失调。设计、合成了一系列 4,5,6,7-四氢-1H-吡唑并[4,3-c]吡啶衍生物，并评估了它们对 c-Met 激酶的酶抑制活性以及对 MKN45、EBC-1 和 PC-3 细胞系的细胞效力。其中九种表现出比通过计算机辅助药物设计发现的先导化合物1更好的活性。其中，化合物 8c 对 c-Met 表现出 68 nM 的抑制活性，对 MKN45 和 EBC-1 细胞系表现出低微摩尔细胞效力。此外，8c 表现出对其他测试的酪氨酸激酶的选择性超过 50 倍。 Western blot结果表明，compound8c能够以剂量依赖的方式抑制MKN45细胞系中c-Met激酶的磷酸化。
c-Met was emerging as an attractive target for cancer-targeted therapy because deregulation of c-Met has been observed in multiple tumor types. A series of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives were designed, synthesized and evaluated for their enzymatic inhibitory activity against c-Met kinase and cellular potency against MKN45, EBC-1 and PC-3 cell lines. Nine of them showed better activity than lead compound1which was found via computer-aided drug design. Among them, compound8cshowed inhibitory activity of 68 nM against c-Met and low micromole cellular potency against MKN45 and EBC-1 cell lines. Moreover,8cdemonstrated more than 50-fold selectivity against other tyrosine kinases tested. The result of western blot indicated that compound8cwas capable of inhibiting the phosphorylation of c-Met kinase in MKN45 cell line in a dose-dependent manner.