PMID: 25742791Mar 7, 2015Paper

Identification of epipolythiodioxopiperazines HDN-1 and chaetocin as novel inhibitor of heat shock protein 90

Oncotarget
Xiaoping SongJing Li

Abstract

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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Citations

Feb 24, 2016·Proceedings of the National Academy of Sciences of the United States of America·Kyungho ParkYoshikazu Uchida
Mar 10, 2017·Expert Opinion on Investigational Drugs·Lizza E L Hendriks, Anne-Marie C Dingemans
Aug 3, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Sicong ZengGe Lin
Nov 30, 2015·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Ming LiuJing Li
Apr 21, 2017·Scientific Reports·Tzu-Tao ChenKang-Yun Lee
Apr 3, 2016·Chemistry : a European Journal·Katherine M ByrdBrian S J Blagg
Sep 1, 2021·European Journal of Pharmacology·Hangyu JiangLin Li

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