Discovery of benzofuran-3(2H)-one derivatives as novel DRAK2 inhibitors that protect islet beta-cells from apoptosis

doi:10.1016/j.ejmech.2017.02.048

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	Discovery of benzofuran-3(2H)-one derivatives as novel DRAK2 inhibitors that protect islet beta-cells from apoptosis
	Wang, Sheng 2; Xu, Lei 3; Lu, Yu-Ting 3; Liu, Yu-Fei 2; Han, Bing ; Liu, Ting 2; Tang, Jie 1,2; Li, Jia3 ; Wu, Jiangping 4; Li, Jing-Ya3
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2017-04-21
卷号	130 页码:195-208
关键词	DRAK2 inhibitor Diabetes Islet beta-cell protection Apoptosis
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2017.02.048
文献子类	Article
英文摘要	Death-associated protein kinase-related apoptosis-inducing kinase-2 (DRAK2) is a serine/threonine kinase that plays a key role in a wide variety of cell death signaling pathways. Inhibition of DRAK2 was found to efficiently protect islet mu-cells from apoptosis and hence DRAK2 inhibitors represent a promising therapeutic strategy for the treatment of diabetes. Only very few chemical entities targeting DRAK2 are currently known. We carried out a high throughput screening and identified compound 4 as a moderate DRAK2 inhibitor with an IC50 value of 3.15 mu M. Subsequent SAR studies of hit compound 4 led to the development of novel benzofuran-3(2H)-one series of DRAK2 inhibitors with improved potency and favorable selectivity profiles against 26 selected kinases. Importantly, most potent compounds 40 (IC50 = 0.33 mu M) and 41 (IC50 = 0.25 mu M) were found to protect islet beta-cells from apoptosis in dosedependent manners. These data support the notion that small molecule inhibitors of DRAK2 represents a promising strategy for the treatment of diabetes. (C) 2017 Elsevier Masson SAS. All rights reserved.
资助项目	National Key Technology R D Program[2015BAK45B00] ; Science and Technology Commission of Shanghai Municipality[16430711700] ; Science and Technology Commission of Shanghai Municipality[16JC1405000] ; Chinese Academy of Sciences[CASIMM0120162021] ; Shanghai Science and Technology Council[16DZ2280100] ; Shanghai Science and Technology Council[15DZ2291600] ; Juvenile Diabetes Foundation[17-2013-440] ; J.Louis Levesque Foundation[00000000] ; Laboratory of Organic Functional Molecules, Sino-French Institute of ECNU[00000000]
WOS关键词	AURONES ; PALMITATE ; KINASE ; OVEREXPRESSION ; DYSFUNCTION ; ACTIVATION ; FAMILY
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:000397180900015
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272695]
专题	国家新药筛选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	Wu, Jiangping; Li, Jing-Ya; Yu, Li-Fang; Yang, Fan
作者单位	1.East China Normal Univ, Shanghai Key Lab Green Chem & Chem Proc, Sch Chem & Mol Engn, 3663 North Zhongshan Rd, Shanghai 200062, Peoples R China; 2.East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Sch Chem & Mol Engn, 3663 North Zhongshan Rd, Shanghai 200062, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Chinese Natl Ctr Drug Screening, State Key Lab Drug Res, 189 Guoshoujing Rd,Zhangjiang Hitech Pk, Shanghai 201203, Peoples R China; 4.Ctr Hosp Univ Montreal, Lab Immunol & Cardiovasc Res, 900 Rue St Denis, Montreal, PQ, Canada
推荐引用方式 GB/T 7714	Wang, Sheng,Xu, Lei,Lu, Yu-Ting,et al. Discovery of benzofuran-3(2H)-one derivatives as novel DRAK2 inhibitors that protect islet beta-cells from apoptosis[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2017,130:195-208.
APA	Wang, Sheng.,Xu, Lei.,Lu, Yu-Ting.,Liu, Yu-Fei.,Han, Bing.,...&Yang, Fan.(2017).Discovery of benzofuran-3(2H)-one derivatives as novel DRAK2 inhibitors that protect islet beta-cells from apoptosis.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,130,195-208.
MLA	Wang, Sheng,et al."Discovery of benzofuran-3(2H)-one derivatives as novel DRAK2 inhibitors that protect islet beta-cells from apoptosis".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 130(2017):195-208.