Identification of novel inhibitors of histone acetyltransferase hMOF through high throughput screening.
Identification of novel inhibitors of histone acetyltransferase hMOF through high throughput screening.
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DOI：
10.1016/j.ejmech.2018.08.026
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发表时间：
2018-09
影响因子：
6.7
通讯作者：
Rukang Zhang;Jiang Wang;Liang Zhao;Shien Liu;Daohai Du;H. Ding;Shijie Chen;Liyan Yue;Yu-Chih Liu;Chen-hua Zhang;Hong Liu;C. Luo
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文献类型：
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作者：
Rukang Zhang;Jiang Wang;Liang Zhao;Shien Liu;Daohai Du;H. Ding;Shijie Chen;Liyan Yue;Yu-Chih Liu;Chen-hua Zhang;Hong Liu;C. Luo
哺乳动物中的组蛋白乙酰转移酶（HAT）包括GCN 5 N-乙酰转移酶、MOZ、YBF 2、SAS 2和TIP 60蛋白以及孤儿HAT。第一次雄性缺失（male absent on the first，MOF）主要与组蛋白H4 Lys 16的乙酰化有关，并影响下游基因的表达。然而，唯一的抑制剂MG 149对MOF表现出低活性。此外，目前还没有针对MOF的高通量筛选平台，限制了抑制剂的发现和功能研究。在本研究中，我们建立了一个高通量的筛选平台，基于放大发光邻近均相分析（ALPHA），这导致我们的中度抑制剂DC_M01。通过化学修饰，我们发现DC_M01_7是DC_M01的类似物，其IC 50值为6 μM。DC_M01_7可显著抑制HCT 116细胞增殖，并能抑制HCT 116细胞组蛋白4赖氨酸16乙酰化。综上所述，我们的工作可能有助于进一步开发更有效的MOF抑制剂和hMOF的功能研究。
The histone acetyltransferases (HATs) in mammals include GCN5N-acetyltransferases, the MOZ, YBF2, SAS2, and TIP60 proteins, and the orphan HATs. The males absent on the first (MOF) is mainly related to acetylation of histone H4 Lys16 and has influence on downstream genes expression. However, the only inhibitor MG149 presented low activity against MOF. Besides, there was no high throughput screening platform on MOF, which limited the inhibitor discovery and functional study. In our study, we set up a high throughput screening platform based on amplified luminescent proximity homogeneous assay (ALPHA), which led us to a moderate inhibitor DC_M01. By chemical modification, we found DC_M01_7, which was the analog of DC_M01 with an IC50value of 6 μM. DC_M01_7 significantly inhibited HCT116 cells proliferation and could also inhibit histone 4 lysine 16 acetylation in HCT116 cells. To sum up, our work will probably assist the further development of more potent MOF inhibitors and the functional study of hMOF.