Discovery of 1,2,4-triazine-based derivatives as novel neddylation inhibitors and anticancer activity studies against gastric cancer MGC-803 cells
Discovery of 1,2,4-triazine-based derivatives as novel neddylation inhibitors and anticancer activity studies against gastric cancer MGC-803 cells
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发现 1,2,4-三嗪类衍生物作为新型 neddylation 抑制剂以及针对胃癌 MGC-803 细胞的抗癌活性研究
DOI：
10.1016/j.bmcl.2019.126791
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发表时间：
2020-01-15
影响因子：
2.7
通讯作者：
Zhang, Sai-Yang
中科院分区：
文献类型：
--
作者：
Song, Jian;Cui, Xin-Xin;Zhang, Sai-Yang
去甲基化修饰通常在多种人类肿瘤细胞中过度表达。因此，靶向去氧途径可能是治疗人类肿瘤的一种潜在途径。在这里，我们描述了从我们内部的库中发现了一个热门的脚手架，并进一步进行了基于结构的优化。在本工作中，化合物V11可抑制NAE活性(EC50值为3.56微米)，并呈剂量依赖性地减少Ubc12-NEDD8的结合。分子对接结果表明，化合物V11可以通过氢键和疏水作用与NAE紧密结合。化合物V11对胃癌MGC-803细胞的抑制作用最强，IC50值为8.22µM。进一步的抗癌活性研究表明，化合物V11抑制MGC-803细胞生长，使细胞周期停滞于G2/M期，并通过外源性和内源性凋亡途径诱导细胞凋亡。这些结果表明，1，2，4-三氮杂环己烷支架可能为进一步开发代谢抑制剂提供了一种新的支架材料，化合物V11可能是一种潜在的具有抗癌活性的代谢抑制剂。
Neddylation modification is often over-expressed in a variety of human tumor cells. Therefore, targeting neddylation pathway may represent a potential approach to the treatment of human tumors. Herein, we describe the discovery of a hit scaffold from our in-house library and further structure-based optimizations. In this work, compound V11 could block the neddylation and inhibit the activity of NAE (with an EC50 value of 3.56 mu M), and a dose-dependent reduction of the Ubc12-NEDD8 conjugations was also observed. Molecular docking results suggest compound V11 could bind tightly to NAE via hydrogen bonds and hydrophobic interactions. Compound V11 showed the best antiproliferative ability with an IC50 value of 8.22 mu M against gastric cancer MGC-803 cells. Further anticancer activity studies suggested that compound V11 inhibited MGC-803 cell growth, caused a cell cycle arrestment at G2/M phase and induced apoptosis via extrinsic and intrinsic apoptosis pathways. All the findings suggest that 1,2,4-triazine scaffold might provide a novel scaffold for the further development of neddylation inhibitors and compound V11 might be a potential neddylation inhibitor with anticancer activity.