| 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
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| 2013 | |
| Source Publication | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| Volume | 59Issue: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. |
| Subtype | Article |
| Keyword | Mcl-1 Small Molecule Inhibitor Fragment-based Approach Anticancer |
| Subject Area | 代谢物组学 |
| WOS Headings | Science & Technology ; Life Sciences & Biomedicine |
| DOI | 10.1016/j.ejmech.2012.10.050 |
| WOS Keyword | SMALL-MOLECULE INHIBITORS ; LEAD DISCOVERY ; BCL-2 PROTEINS ; DRUG DISCOVERY ; SOLUBILITY ; DESIGN ; LIGAND ; DEGRADATION ; APOPTOSIS ; MIXTURES |
| Indexed By | SCI ; IC |
| Language | 英语 |
| WOS Research Area | Pharmacology & Pharmacy |
| WOS Subject | Chemistry, Medicinal |
| WOS ID | WOS:000315554100016 |
| Citation statistics | |
| Document Type | 期刊论文 |
| Identifier | http://ir.qibebt.ac.cn/handle/337004/1689 |
| Collection | 代谢物组学研究组 |
| Affiliation | 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 |
| 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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