Discovery of novel trimethoxy-ring BRD4 bromodomain inhibitors: AlphaScreen assay, crystallography and cell-based assay

doi:10.1039/c7md00083a

	Discovery of novel trimethoxy-ring BRD4 bromodomain inhibitors: AlphaScreen assay, crystallography and cell-based assay
	Chen, Zhifeng1,2,3 ; Zhang, Hao 1,3; Liu, Shien 1,3; Xie, Yiqian 4; Jiang, Hao 1,3; Lu, Wenchao 1,3; Xu, Heng 1,3; Yue, Liyan 1,3; Zhang, Yuanyuan 1; Ding, Hong 1,4; Zheng, Mingyue 1; Yu, Kunqian 1; Chen, Kaixian 1; Jiang, Hualiang1,2,3 ; Luo, Cheng 1,3
	2017-06
发表期刊	MEDCHEMCOMM (IF:5.121[JCR-2021],3.796[5-Year])
ISSN	2040-2503
卷号	8 期号:6 页码:1322-1331
发表状态	已发表
DOI	10.1039/c7md00083a
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.
收录类别	SCI
语种	英语
资助项目	State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science[TMC201505]
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy
WOS类目	Biochemistry & Molecular Biology ; Chemistry, Medicinal
WOS记录号	WOS:000404076200021
出版者	ROYAL SOC CHEMISTRY
WOS关键词	BET BROMODOMAINS ; DRUG DISCOVERY ; LEUKEMIA ; CANCER ; POTENT ; OPTIMIZATION ; RECOGNITION ; DERIVATIVES ; CHROMATIN ; DENSITY
原始文献类型	Article
通讯作者	Zhang, Yuanyuan ; Ding, Hong ; Luo, Cheng
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/2925
专题	生命科学与技术学院免疫化学研究所_特聘教授组_蒋华良组生命科学与技术学院_硕士生
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
第一作者单位	生命科学与技术学院
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.