化学
苯甲酰胺
热休克蛋白90
结肠炎
IC50型
溃疡性结肠炎
部分
药理学
结构-活动关系
生物化学
癌症研究
体外
立体化学
疾病
免疫学
基因
生物
病理
热休克蛋白
医学
作者
Jiang Fen,An-ping Guo,Jiachen Xu,Qidong You,Xiu Xu
标识
DOI:10.1021/acs.jmedchem.8b00800
摘要
As the endoplasmic reticulum paralogue of Hsp90, Grp94 chaperones a small set of client proteins associated with some diseases, including cancer, primary open-angle glaucoma, and inflammatory disorders. Grp94-selective inhibition has been a potential therapeutic strategy for these diseases. In this study, inspired by the conclusion that ligand-induced “Phe199 shift” effect is the structural basis of Grp94-selective inhibition, a series of novel Grp94 selective inhibitors incorporating “benzamide” moiety were developed, among which compound 54 manifested the most potent Grp94 inhibitory activity with an IC50 value of 2 nM and over 1000-fold selectivity to Grp94 against Hsp90α. In a DSS-induced mouse model of ulcerative colitis (UC), compound 54 exhibited significant anti-inflammatory efficacy. This work provides a potent Grp94 selective inhibitor as probe compound for the biological study of Grp94 and represents the first study that confirms the potential therapeutic efficacy of Grp94-selective inhibitors against UC.
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