Design, synthesis and biological activities of pyrrole-3-carboxamide derivatives as EZH2 (enhancer of zeste homologue 2) inhibitors and anticancer agents,New Journal of Chemistry

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Design, synthesis and biological activities of pyrrole-3-carboxamide derivatives as EZH2 (enhancer of zeste homologue 2) inhibitors and anticancer agents
New Journal of Chemistry ( IF 2.7 ) Pub Date : 2020/01/10 , DOI: 10.1039/c9nj04713a
Qifan Zhou _{1,

2,

3,

4,

5} , Lina Jia _{3,

4,

5,

6} , Fangyu Du _{1,

2,

3,

4,

5} , Xiaoyu Dong _{3,

4,

5,

6} , Wanyu Sun _{3,

4,

5,

6} , Lihui Wang _{3,

4,

5,

6} , Guoliang Chen _{1,

2,

3,

4,

5}

Affiliation

Zeste enhancer homolog 2 (EZH2) is highly expressed in various malignant tumors, which could silence tumor suppressor genes via trimethylation of H3K27. Herein was first reported a novel series of pyrrole-3-carboxamide derivatives carrying a pyridone fragment as EZH2 inhibitors. By combining computational modeling, in vitro cellular assays and further rational structure–activity relationship exploration and optimization, compound DM-01 showed powerful inhibition towards EZH2. DM-01 was found to have significant ability to reduce the cellular H3K27me3 level in K562 cells in the Western blot test. Meanwhile, our data showed that knockdown EZH2 in A549 cells resulted in a decrease of cell sensitivity to DM-01 at 50 and 100 μM. DM-01 could also increase the transcription expression of DIRAS3 in a dose-dependent manner, a tumor suppressor in the downstream of EZH2, suggesting it was worth investigating further as a lead compound.

中文翻译：

吡咯-3-甲酰胺衍生物作为EZH2（zeste同源物2的增强剂）抑制剂和抗癌剂的设计，合成和生物学活性

Zeste增强子同源物2（EZH2）在各种恶性肿瘤中高表达，可以通过H3K27的三甲基化沉默沉默抑癌基因。本文首先报道了一系列带有吡啶酮片段作为EZH2抑制剂的吡咯-3-羧酰胺衍生物。通过将计算模型，体外细胞分析以及进一步的合理的构效关系探索和优化相结合，化合物DM-01对EZH2具有强大的抑制作用。在蛋白质印迹试验中，发现DM-01具有降低K562细胞中细胞H3K27me3水平的显着能力。同时，我们的数据显示，敲低A549细胞中的EZH2导致细胞对DM-01的敏感性降低在50和100μM下 DM-01还可以以剂量依赖的方式增加DIRAS3的转录表达，这是EZH2下游的一种抑癌剂，表明它有必要进一步研究作为先导化合物。

更新日期：2020-02-12

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