Terephthalamide Derivatives as Mimetics of Helical Peptides: Disruption of the Bcl-xL/Bak Interaction
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- 作者：Hang Yin ; Gui-in Lee ; Kristine A. Sedey ; Johanna M. Rodriguez ; Hong-Gang Wang ; Said M. Sebti ; and Andrew D. Hamilton
- 刊名：Journal of the American Chemical Society
- 出版年：2005
- 出版时间：April 20, 2005
- 年：2005
- 卷：127
- 期：15
- 页码：5463 - 5468
- 全文大小：286K
- 年卷期：v.127,no.15(April 20, 2005)
- ISSN：1520-5126
文摘
A series of Bcl-xL/Bak antagonists, based on a terephthalamide scaffold, was designed to mimicthe 
mages/gifchars/alpha.gif" BORDER=0>-helical region of the Bak peptide. These molecules showed favorable in vitro activities in disruptingthe Bcl-xL/Bak BH3 domain complex (terephthalamides 9 and 26, Ki = 0.78 ± 0.07 and 1.85 ± 0.32 mages/entities/mgr.gif">M,respectively). Extensive structure-affinity studies demonstrated a correlation between the ability ofterephthalamide derivatives to disrupt Bcl-xL/Bak complex formation and the size of variable side chainson these molecules. Treatment of human HEK293 cells with the terephthalamide derivative 26 resulted indisruption of the Bcl-xL/Bax interaction in whole cells with an IC50 of 35.0 mages/entities/mgr.gif">M. Computational dockingsimulations and NMR experiments suggested that the binding cleft for the BH3 domain of the Bak peptideon the surface of Bcl-xL is the target area for these synthetic inhibitors.