Discovery of 8-Methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors

doi:10.1021/acs.jmedchem.9b01784

	Discovery of 8-Methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors
	Li, Zizhou 1,2; Xiao, Senhao 2,3,4; Yang, Yaxi 1,2; Chen, Chao 1,2; Lu, Tian 2,3; Chen, Zhifeng 3; Jiang, Hualiang 3; Chen, Shijie 3; Luo, Cheng 2,3; Zhou, Bing 1
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2020-04-23
卷号	63 期号:8 页码:3956-3975
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.9b01784
通讯作者	Luo, Cheng(cluo@simm.ac.cn) ; Zhou, Bing(zhoubing@simm.ac.cn)
英文摘要	The bromodomain and extra-terminal (BET) family proteins have recently emerged as promising drug targets for cancer therapy. In this study, identification of an 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one fragment (47) as a new binder to the BET bromodomains and the subsequent incorporation of fragment 47 to the scaffold of ABBV-075, which recently entered Phase I clinical trials, enabled the generation of a series of highly potent BET bromodomain inhibitors. Further druggability optimization led to the discovery of compound 38 as a potential preclinical candidate. Significantly, compared with ABBV-075, which exhibits a 63-fold selectivity for BRD4(1) over EP300, compound 38 demonstrates an excellent selectivity for the BET bromodomain family over other bromodomains, with an similar to 1500-fold selectivity for BRD4(1) over EP300. Orally administered 38 achieves a complete inhibition of tumor growth with a tumor growth inhibition (TGI) of 99.7% accompanied by good tolerability.
资助项目	National Natural Science Foundation of China[81973166] ; National Natural Science Foundation of China[91753207] ; National Natural Science Foundation of China[21702218] ; National Natural Science Foundation of China[81773568] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81821005] ; National Key R&D Program of China[2018YFA0508200] ; 1000-Youth Talents Plan ; Science and Technology Commission of Shanghai Municipality[17QA1405000] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[19XD1404700] ; K.C. Wong Education Foundation ; Youth innovation promotion association[2017333] ; National Science and Technology Major Project[2018ZX09711002-004-012] ; National Science and Technology Major Project[2018ZX09711002006-001] ; National Science and Technology Major Project[2018ZX09711002-008-005]
WOS关键词	BRD4 ; FAMILY ; IDENTIFICATION ; CANDIDATE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000529170200010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/280570]
专题	中国科学院上海药物研究所
通讯作者	Luo, Cheng; Zhou, Bing
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, 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	Li, Zizhou,Xiao, Senhao,Yang, Yaxi,et al. Discovery of 8-Methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2020,63(8):3956-3975.
APA	Li, Zizhou.,Xiao, Senhao.,Yang, Yaxi.,Chen, Chao.,Lu, Tian.,...&Zhou, Bing.(2020).Discovery of 8-Methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,63(8),3956-3975.
MLA	Li, Zizhou,et al."Discovery of 8-Methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 63.8(2020):3956-3975.