Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays
文献类型：期刊论文
| 作者 | Sun, Zhongya2; Zhang, Hao3,4; Chen, Zhifeng1; Xie, Yiqian3; Jiang, Hao3; Chen, Limin2; Ding, Hong3 ; Zhang, Yuanyuan3; Jiang, Hualiang3; Zheng, Mingyue3
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
 |
| 出版日期 | 2017-05-01 |
| 卷号 | 27期号:9页码:2003-2009 |
| 关键词 | BRD4 inhibitor High-throughput screening Crystallography |
| ISSN号 | 0960-894X |
| DOI | 10.1016/j.bmcl.2017.03.012 |
| 文献子类 | Article |
| 英文摘要 | As an epigenetic reader, BRD4 regulates the transcription of important downstream genes that are essential for the survival of tumor cells. Small molecular inhibitors targeting the first bromodomain of BRD4 (BRD4-BD1) have showed promising potentials in the therapies of BRD4-related cancers. Through AlphaScreen-based high-throughput screening assay, a novel small molecular inhibitor was identified, and named DCBD-005, which inhibited the binding between BRD4-BD1 and acetylated lysines with an IC50 value of 0.81 +/- 0.03 mu M. The compound DCBD-005 effectively inhibited the viability, caused cell cycle arrest, and induced apoptosis in human leukemia MV4-11 cells. Moreover, the crystal structure of compound DCBD-005 with the BRD4-BD1 was determined at 1.72 angstrom resolution, which revealed the binding mechanism of the leading compound, and also provided solid basis for further structure-based optimization. These results indicated that this novel BRD4-BD1 inhibitor DCBD-005 is promising to be developed into a drug candidate in the treatment of BRD4-related diseases. (C) 2017 Published by Elsevier Ltd. |
| WOS关键词 | BET BROMODOMAIN INHIBITION ; GENE-EXPRESSION ; CHROMATIN ; TARGET ; CANCER ; POTENT ; OPTIMIZATION ; ACETYLATION ; RECOGNITION ; ACTIVATION |
| 资助项目 | Computer Network Information Center, Chinese Academy of Sciences[00000000] ; Guangdong Supercomputing Center[2015-446] ; Ministry of Science and Technology of China[2015CB910304] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[91229205] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[21210003] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[81430084] ; Fund of State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science[TMC201505] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000399862800025 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272688]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Chen, Limin; Ding, Hong; Luo, Cheng |
| 作者单位 | 1.ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China 2.Nanchang Univ, Sch Pharm, 461 Bayi Rd, Nanchang 330006, Jiangxi, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 4.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Sun, Zhongya,Zhang, Hao,Chen, Zhifeng,et al. Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2017,27(9):2003-2009. |
| APA | Sun, Zhongya.,Zhang, Hao.,Chen, Zhifeng.,Xie, Yiqian.,Jiang, Hao.,...&Luo, Cheng.(2017).Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,27(9),2003-2009. |
| MLA | Sun, Zhongya,et al."Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 27.9(2017):2003-2009. |
入库方式： OAI收割
来源：上海药物研究所
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