Discovery of novel trimethoxy-ring BRD4 bromodomain inhibitors: AlphaScreen assay, crystallography and cell-based assay
文献类型：期刊论文
| 作者 | Chen, Zhifeng1,2,3; Zhang, Hao1,3; Liu, Shien1,3; Xie, Yiqian4; Jiang, Hao1,3; Lu, Wenchao1,3; Xu, Heng1,3; Yue, Liyan1,3; Zhang, Yuanyuan1; Ding, Hong1,4
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| 刊名 | MEDCHEMCOMM
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| 出版日期 | 2017-06-01 |
| 卷号 | 8期号:6页码:1322-1331 |
| ISSN号 | 2040-2503 |
| DOI | 10.1039/c7md00083a |
| 文献子类 | Article |
| 英文摘要 | As a member of the bromodomain and extra terminal domain ( BET) protein family, BRD4 is closely related to cancers and other diseases. Small-molecule BRD4 inhibitors have already demonstrated promising potential for the therapy of BRD4-related cancers. In this study, we report the discovery and evaluation of a novel category of BRD4 inhibitors, which share a trimethoxy ring and target the first bromodomain of the human BRD4 protein. The IC50 value of the most potent compound, DC-BD-03, is 2.01 mu M. In addition, a high-resolution crystal structure of the compound DC-BD-29 with the first bromodomain of BRD4 was determined, which revealed the binding mode and facilitated further structure-based optimization. These compounds exhibited anti-proliferation activity, caused cell cycle arrest, and induced apoptosis in human leukemia MV4-11 cells. Thus, the results presented in this study indicated the potential of this series of compounds as drug candidates for the therapy of BRD4-related cancers. |
| WOS关键词 | BET BROMODOMAINS ; DRUG DISCOVERY ; LEUKEMIA ; CANCER ; POTENT ; OPTIMIZATION ; RECOGNITION ; DERIVATIVES ; CHROMATIN ; DENSITY |
| 资助项目 | Ministry of Science and Technology of China[2015CB910304] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[21210003] ; National Natural Science Foundation of China[81230076] ; State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science[TMC201505] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000404076200021 |
| 出版者 | ROYAL SOC CHEMISTRY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272638]  |
| 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 | Zhang, Yuanyuan; Ding, Hong; Luo, Cheng |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 2.ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China; 3.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China; 4.Shanghai Univ Tradit Chinese Med, Sch Pharm, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Zhifeng,Zhang, Hao,Liu, Shien,et al. Discovery of novel trimethoxy-ring BRD4 bromodomain inhibitors: AlphaScreen assay, crystallography and cell-based assay[J]. MEDCHEMCOMM,2017,8(6):1322-1331. |
| APA | Chen, Zhifeng.,Zhang, Hao.,Liu, Shien.,Xie, Yiqian.,Jiang, Hao.,...&Luo, Cheng.(2017).Discovery of novel trimethoxy-ring BRD4 bromodomain inhibitors: AlphaScreen assay, crystallography and cell-based assay.MEDCHEMCOMM,8(6),1322-1331. |
| MLA | Chen, Zhifeng,et al."Discovery of novel trimethoxy-ring BRD4 bromodomain inhibitors: AlphaScreen assay, crystallography and cell-based assay".MEDCHEMCOMM 8.6(2017):1322-1331. |
入库方式： OAI收割
来源：上海药物研究所
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