期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 46, 期 9, 页码 3909-3916出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2011.05.062
关键词
Apoptosis; Mcl-1; Bcl-2; p2 pocket; Dual inhibitor
资金
- Fundamental Research Funds for the Central Universities
- National Natural Science Foundation of China [30772622]
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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