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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, Zhichao1; Song, Ting2,3; Li, Xiangqian1; Wu, Zhiyong1; Feng, Yingang4; Xie, Feibo1; Liu, Chengwu1; Qin, Jianquan3; Chen, Hongbo1
2013
Source PublicationEUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume59Issue:59Pages:141-149
Abstract 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).
 
 
 
; 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.
SubtypeArticle
KeywordMcl-1 Small Molecule Inhibitor Fragment-based Approach Anticancer
Subject Area代谢物组学
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
DOI10.1016/j.ejmech.2012.10.050
WOS KeywordSMALL-MOLECULE INHIBITORS ; LEAD DISCOVERY ; BCL-2 PROTEINS ; DRUG DISCOVERY ; SOLUBILITY ; DESIGN ; LIGAND ; DEGRADATION ; APOPTOSIS ; MIXTURES
Indexed BySCI ; IC
Language英语
WOS Research AreaPharmacology & Pharmacy
WOS SubjectChemistry, Medicinal
WOS IDWOS:000315554100016
Citation statistics
Cited Times:18[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.qibebt.ac.cn/handle/337004/1689
Collection代谢物组学研究组
Affiliation1.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
Recommended Citation
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.
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