Probing the difference between BH3 groove of Mcl-1 and Bcl-2 protein: Implications for dual inhibitors design
发表时间：2019-03-09
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- 论文类型：
- 期刊论文
- 第一作者：
- Zhang, Zhichao
- 通讯作者：
- Zhang, ZC (reprint author), Dalian Univ Technol, State Key Lab Fine Chem, Sch Chem, Dalian 116012, Peoples R China.
- 合写作者：
- Yang, Hongna,Wu, Guiye,Li, Zhiqiang,Song, Ting,Li, Xiang Qian
- 发表时间：
- 2011-09-01
- 发表刊物：
- EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
- 收录刊物：
- Scopus、SCIE、PubMed
- 文献类型：
- J
- 卷号：
- 46
- 期号：
- 9
- 页面范围：
- 3909-3916
- ISSN号：
- 0223-5234
- 关键字：
- Apoptosis; Mcl-1; Bcl-2; p2 pocket; Dual inhibitor
- 摘要：
- Based on our previous discovery of a dual inhibitor of Mcl-1 and Bcl-2, 3-thiomorpholin-8-oxo-8H-acenaphthol[,2-b]pyrrole-9-carbonitrile (1, S1), and guided by structure insight of 1 complex with Mcl-1 and Bcl-2, we exploited the spatial orientation of BH3 groove of the two proteins by a series of analogues of 1. These analogues contain substitutes with various steric hindrance designed to explore the width and length of the p2 pocket. The structure-activity relationships (SARs) studies together with docking studies and cell-based assays proved that the p2 pocket of Mcl-1 is relatively wider and shorter than that of Bcl-2. A novel dual inhibitor 6 was obtained based on these new findings that it exhibited nanomalar affinities toward Mcl-1 and Bcl-2, as well as nanomalar cytotoxicity activity against multiple cancer cell lines. (C) 2011 Elsevier Masson SAS. All rights reserved.
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- 否
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