Novel soluble myeloid cell leukemia sequence 1 (Mcl-1) inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g) developed using a fragment-based approach

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	Novel soluble myeloid cell leukemia sequence 1 (Mcl-1) inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g) developed using a fragment-based approach
	Zhang, Zhichao 1; Song, Ting 2,3; Li, Xiangqian 1; Wu, Zhiyong 1; Feng, Yingang 4; Xie, Feibo 1; Liu, Chengwu 1; Qin, Jianquan 3; Chen, Hongbo 1
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2013
卷号	59 期号:59 页码:141-149
关键词	Mcl-1 Small molecule inhibitor Fragment-based approach Anticancer
中文摘要	Based on a known nanomolar Bcl-2 homology domain 3 (BH3) mimetic 3-thiomorpholin-8-oxo-8Hacenaphtho[1,2-b] pyrrole-9-carbonitrile (S1,MW: 331), we applied a fragment-based approach to obtainBH3 mimetics with improved affinity and improved solubility in a watereethanol (9:1) cosolvent. After the deconstruction of 1 (S1), we obtained fragment cyanoacetamide (4), which was determined to be a ligand efficiency (LE) hot part. After a rational optimization through fragment evolution beginning with fragment 4, a smaller Mcl-1 inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g, MW: 288) with a 6-fold increase in affinity compared to 1 was obtained, as predicted by our optimization curve and identified by Mcl-1 protein nuclear magnetic resonance (NMR).
英文摘要	Based on a known nanomolar Bcl-2 homology domain 3 (BH3) mimetic 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b] pyrrole-9-carbonitrile (SI, MW: 331), we applied a fragment-based approach to obtain BH3 mimetics with improved affinity and improved solubility in a water ethanol (9:1) cosolvent. After the deconstruction of 1 (S1), we obtained fragment cyanoacetamide (4), which was determined to be a ligand efficiency (LE) hot part. After a rational optimization through fragment evolution beginning with fragment 4, a smaller Mcl-1 inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g, MW: 288) with a 6-fold increase in affinity compared to I was obtained, as predicted by our optimization curve and identified by Mcl-1 protein nuclear magnetic resonance (NMR). (C) 2012 Elsevier Masson SAS. All rights reserved.
学科主题	代谢物组学
WOS标题词	Science & Technology ; Life Sciences & Biomedicine
类目[WOS]	Chemistry, Medicinal
研究领域[WOS]	Pharmacology & Pharmacy
关键词[WOS]	SMALL-MOLECULE INHIBITORS ; LEAD DISCOVERY ; BCL-2 PROTEINS ; DRUG DISCOVERY ; SOLUBILITY ; DESIGN ; LIGAND ; DEGRADATION ; APOPTOSIS ; MIXTURES
收录类别	SCI ; IC
语种	英语
WOS记录号	WOS:000315554100016
公开日期	2014-03-24
内容类型	期刊论文
源URL	[http://ir.qibebt.ac.cn:8080/handle/337004/1689]
专题	青岛生物能源与过程研究所_代谢物组学团队
作者单位	1.Dalian Univ Technol, Sch Chem, State Key Lab Fine Chem, Dalian 116012, Peoples R China 2.Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China 3.Dalian Univ Technol, Sch Life Sci & Technol, Dalian 116024, Peoples R China 4.Chinese Acad Sci, Qingdao Inst BioEnergy & Bioproc Technol, Qingdao 266101, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Zhichao,Song, Ting,Li, Xiangqian,et al. Novel soluble myeloid cell leukemia sequence 1 (Mcl-1) inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g) developed using a fragment-based approach[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2013,59(59):141-149.
APA	Zhang, Zhichao.,Song, Ting.,Li, Xiangqian.,Wu, Zhiyong.,Feng, Yingang.,...&Chen, Hongbo.(2013).Novel soluble myeloid cell leukemia sequence 1 (Mcl-1) inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g) developed using a fragment-based approach.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,59(59),141-149.
MLA	Zhang, Zhichao,et al."Novel soluble myeloid cell leukemia sequence 1 (Mcl-1) inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g) developed using a fragment-based approach".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 59.59(2013):141-149.