Design, synthesis and biological evaluation of benzo[cd]indo1-2(1H)-ones derivatives as BRD4 inhibitors

doi:10.1016/j.ejmech.2018.04.048

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	Design, synthesis and biological evaluation of benzo[cd]indo1-2(1H)-ones derivatives as BRD4 inhibitors
	Feng, Yuxin 2; Xiao, Senhao 1,3,4; Chen, Yantao 1,3; Jiang, Hao 1,3; Liu, Na 2; Luo, Cheng1,3 ; Chen, Shijie 1,3; Chen, Hua 2
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2018-05-25
卷号	152 页码:264-273
关键词	Benzo[cd]indol-2(1H)-one Sulfonamide BRD4 inhibitor Bromodomain and extra-terminal domain Acetyl-lysine binding pocket
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2018.04.048
文献子类	Article
英文摘要	Compound 1 bearing with benzo [cd]indo1-2(1H)-one scaffold was identified as an effective BRD4 inhibitor through the AlphaScreen-based high-throughput screening and its high-resolution crystal structure with BRD4_BD1 protein. A series of 48 compounds were designed and synthesized by structural optimization on compound 1. All the compounds have been evaluated for their BRD4 inhibitory activities. The results showed that compounds 23, 24, 28 and 44 are the most potential ones with the IC50 values of 1.02 mu M,1.43 mu M,1.55 mu M and 3.02 mu M, respectively. According to their co-crystal structures in complex with BRD4_BD1 and the protein thermal shift assays, the binding modes were revealed that the additional indirect hydrogen bonds and hydrophobic interactions make such four compounds more active than 1 against BRD4. Furthermore, compounds 1, 23 and 44 were chosen to evaluate for their antiproliferative activities on the MLL-AF4-expression acute leukemia cell line (MV4-11), other cancer cell lines (MDA-MB-231, A549, 22Rv1) and the non-cancer cell lines (HUV-EC-C, MRCS, RPTEC). The results showed that these compounds exhibited good and selective inhibitory activities against MV4-11 cells with the IC50 values of 11.67 mu M, 5.55 mu M, and 11.54 mu M, respectively, and could act on the cell proliferation by blocking cell cycle at G1 phase. They could markedly down-regulate the expressions of the c-Myc, BcI-2 and CDK6 oncogenes in MV4-11 in the qRT-PCR and western blot studies, which further demonstrated that compound 1 and its derivatives could serve as a promising therapeutic strategy for MLL leukemia by targeting BRD4_BD1 protein. (C) 2018 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[81703415] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81625022] ; Shanghai Sailing Program[17YF1423100]
WOS关键词	BET BROMODOMAINS ; DISCOVERY ; FAMILY ; OPTIMIZATION ; CHROMATIN ; I-BET151 ; LEUKEMIA ; READER ; DOMAIN ; SERIES
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000435048900021
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279743]
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, Shijie; Chen, Hua
作者单位	1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 2.Hebei Univ, Coll Chem & Environm Sci, Key Lab Chem Biol Hebei Prov, Baoding 071002, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst MateriaMed, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China
推荐引用方式 GB/T 7714	Feng, Yuxin,Xiao, Senhao,Chen, Yantao,et al. Design, synthesis and biological evaluation of benzo[cd]indo1-2(1H)-ones derivatives as BRD4 inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,152:264-273.
APA	Feng, Yuxin.,Xiao, Senhao.,Chen, Yantao.,Jiang, Hao.,Liu, Na.,...&Chen, Hua.(2018).Design, synthesis and biological evaluation of benzo[cd]indo1-2(1H)-ones derivatives as BRD4 inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,152,264-273.
MLA	Feng, Yuxin,et al."Design, synthesis and biological evaluation of benzo[cd]indo1-2(1H)-ones derivatives as BRD4 inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 152(2018):264-273.