Identification of epipolythiodioxopiperazines HDN-1 and chaetocin as novel inhibitor of heat shock protein 90.
Identification of epipolythiodioxopiperazines HDN-1 and chaetocin as novel inhibitor of heat shock protein 90.
复制标题
表聚硫二氧代哌嗪 HDN-1 和毛壳素作为新型热休克蛋白 90 抑制剂的鉴定
DOI：
10.18632/oncotarget.3029
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发表时间：
2015-03-10
期刊：
影响因子：
--
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Song X;Zhao Z;Qi X;Tang S;Wang Q;Zhu T;Gu Q;Liu M;Li J
分子伴侣热休克蛋白90（Hsp90）已成为癌症治疗的一个重要靶点。HDN - 1是一种表聚硫代哌嗪 - 2,5 - 二酮（ETPs）化合物，在此被鉴定为一种新的Hsp90抑制剂。HDN - 1直接与Hsp90α的C末端结合，导致潜在的构象变化，干扰了17 - AAG和新生霉素与Hsp90α的结合。相反，17 - AAG、新生霉素或ATP与Hsp90α的结合并不能阻止HDN - 1与Hsp90α的结合。HDN - 1与17 - AAG联合对非小细胞肺癌细胞增殖表现出增强的抑制作用。分子对接分析显示，HDN - 1在C末端526 - 570区域与Hsp90α结合。此外，HDN - 1降解多种癌蛋白，并促进表皮生长因子诱导的野生型和突变型表皮生长因子受体下调。值得注意的是，毛壳菌素作为一种与HDN - 1结构相似的SUV39H1抑制剂，与Hsp90结合，像HDN - 1一样降解Hsp90客户蛋白和SUV39H1。这些结果表明，HDN - 1和毛壳菌素是Hsp90的抑制剂，并且SUV39H1是Hsp90的一种新型客户蛋白。
The molecular chaperone heat shock protein 90 (Hsp90) has emerged as an important target for cancer treatment. HDN-1, an epipolythiopiperazine-2, 5-diones (ETPs) compound, was here identified as a new Hsp90 inhibitor. HDN-1 bound directly to C-terminus of Hsp90α, resulting in a potential conformational change that interfered with the binding of 17-AAG and novobiocin to Hsp90α. In contrast, association of 17-AAG, novobiocin or ATP with Hsp90α did not prevent the binding HDN-1 to Hsp90α. HDN-1 in combination with 17-AAG exhibited an enhanced inhibitory effect on non-small lung cancer cell proliferation. Molecular docking analyses revealed that HDN-1 bound to Hsp90α at C-terminal 526–570 region. In addition, HDN-1 degraded multiple oncoproteins and promoted EGF-induced wild type and mutated EGFR downregulation. Notably, chaetocin, used as a SUV39H1 inhibitor with similar structure to HDN-1, bound to Hsp90 and degraded Hsp90 client proteins and SUV39H1 as did HDN-1. These results indicate that HDN-1 and chaetocin are inhibitors of Hsp90 and that SUV39H1 is a novel client protein of Hsp90.
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