Terephthalamide derivatives as mimetics of helical peptides:: Disruption of the Bcl-xL/Bak interaction
Terephthalamide derivatives as mimetics of helical peptides:: Disruption of the Bcl-xL/Bak interaction
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DOI：
10.1021/ja0446404
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发表时间：
2005-04-20
影响因子：
15
通讯作者：
Hamilton, AD
中科院分区：
文献类型：
--
作者：
Yin, H;Lee, GI;Hamilton, AD
一系列基于对苯二甲酰胺支架的 Bcl-x(L)/Bak 拮抗剂旨在模拟 Bak 肽的 cc 螺旋区域。这些分子在破坏 Bcl-xL/Bak BH3 结构域复合物（对苯二甲酰胺 9 和 26，K-i 分别 = 0.78 +/- 0.07 和 1.85 +/- 0.32 μM）方面表现出良好的体外活性。广泛的结构亲和力研究表明，对苯二甲酰胺衍生物破坏 Bcl-xL/Bak 复合物形成的能力与这些分子上可变侧链的大小之间存在相关性。用对苯二甲酰胺衍生物 26 处理人 HEK293 细胞会破坏整个细胞中的 Bcl-x(L)/Bax 相互作用，IC50 为 35.0 mu M。计算对接模拟和 NMR 实验表明，Bcl-x(L) 表面 Bak 肽的 BH3 结构域的结合裂缝是这些合成抑制剂的目标区域。
A series of Bcl-x(L)/Bak antagonists, based on a terephthalamide scaffold, was designed to mimic the cc-helical region of the Bak peptide. These molecules showed favorable in vitro activities in disrupting ;the Bcl-xL/Bak BH3 domain complex (terephthalamides 9 and 26, K-i = 0.78 +/- 0.07 and 1.85 +/- 0.32 mu M, respectively). Extensive structure-affinity Studies demonstrated a correlation between the ability of terephthalamide derivatives to disrupt Bcl-xL/Bak complex formation and the size of variable side chains on these molecules. Treatment of human HEK293 cells with the terephthalamide derivative 26 resulted in disruption of the Bcl-x(L)/Bax interaction in whole cells with an IC50 of 35.0 mu M. Computational docking simulations and NMR experiments suggested that the binding cleft for the BH3 domain of the Bak peptide on the surface of Bcl-x(L) is the target area for these synthetic inhibitors.