Development and evaluation of a novel series of Nitroxoline-derived BET inhibitors with antitumor activity in renal cell carcinoma

doi:10.1038/s41389-018-0093-z

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	Development and evaluation of a novel series of Nitroxoline-derived BET inhibitors with antitumor activity in renal cell carcinoma
	Chen, Wei 1; Zhang, Hao 2,3; Chen, Zhifeng 2; Jiang, Hao 2,3; Liao, Liping 2,3; Fan, Shijie 4; Xing, Jing 2,3; Xie, Yiqian 2; Chen, Shijie 2; Ding, Hong2
刊名	ONCOGENESIS
	2018-11-02
卷号	7
ISSN号	2157-9024
DOI	10.1038/s41389-018-0093-z
文献子类	Article
英文摘要	Small molecular inhibitors targeting BRD4 family proteins are emerging as promising therapies in many types of human malignancies. However, whether BRD4, as well as other BET family members, may serve as therapeutic targets in renal cell carcinoma (RCC) remains unknown. In this study, we found that both BRD2 and BRD4 were over-expressed in RCC tissues, knock-down both of which achieved potent anti-proliferative effects in RCC cells. A novel category of BET inhibitors, originated from an approved drug Nitroxoline, were synthesized and evaluated with biochemical and cellular assays, as well as the method of crystallography. The complex crystal structures of several compounds in this category with the first bromodomain of BRD4 (BRD4-BD1) were solved, revealing the binding mechanism and facilitating further structural optimizations. Among them, compound BDF-1253 showed an approximately four-fold improvement in BRD4 inhibition compared with the prototype Nitroxoline and had good selectivity for BET proteins against other bromodomain proteins or epi-enzymes in biochemical assays. Compound BDF-1253 efficiently suppressed the expression of BET downstream genes, impaired RCC cells viability via inducing cell cycle arrest and apoptosis, and decreased tumor growth in RCC xenografts. In summary, these results suggest that inhibition of BET family members has great therapeutic potentials in the treatment of RCC, and the novel series of BET inhibitors reported here are promising to become RCC drug candidates.
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[81625022] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[81803554] ; Chinese Academy of Sciences[XDA12020353]
WOS关键词	C-MYC ; CANCER ; BRD4 ; DISCOVERY ; BROMODOMAINS ; LEUKEMIA ; TARGET ; IDENTIFICATION ; PROLIFERATION ; TRANSCRIPTION
WOS研究方向	Oncology
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000449930700001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279499]
专题	药物发现与设计中心
通讯作者	Zheng, Mingyue; Huang, Yiran; Zhang, Yuanyuan
作者单位	1.Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Urol, 160 Pujian Rd, Shanghai 200127, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 4.China Pharmaceut Univ, Sch Pharm, Nanjing 210009, Jiangsu, Peoples R China; 5.Shanghai Inst Technol, Coll Chem & Environm Engn, Shanghai 210032, Peoples R China
推荐引用方式 GB/T 7714	Chen, Wei,Zhang, Hao,Chen, Zhifeng,et al. Development and evaluation of a novel series of Nitroxoline-derived BET inhibitors with antitumor activity in renal cell carcinoma[J]. ONCOGENESIS,2018,7.
APA	Chen, Wei.,Zhang, Hao.,Chen, Zhifeng.,Jiang, Hao.,Liao, Liping.,...&Zhang, Yuanyuan.(2018).Development and evaluation of a novel series of Nitroxoline-derived BET inhibitors with antitumor activity in renal cell carcinoma.ONCOGENESIS,7.
MLA	Chen, Wei,et al."Development and evaluation of a novel series of Nitroxoline-derived BET inhibitors with antitumor activity in renal cell carcinoma".ONCOGENESIS 7(2018).