Discovery of a Potent Grp94 Selective Inhibitor with Anti-Inflammatory Efficacy in a Mouse Model of Ulcerative Colitis.

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.

Identification and optimization of novel 6-acylamino-2-aminoquinolines as potent Hsp90 C-terminal inhibitors.

In order to discover novel Hsp90 inhibitors targeting the C-terminal ATP binding pocket, a novobiocin derivative based ROCS model was constructed for virtual screening. Compound 13 was identified as the lead compound and then systematical structure activity relationship (SAR) study was conducted. These efforts led to compound 69, which exhibited potent anti-proliferative activities against MCF7 and SKBr3 breast cancer cell lines. In 4T1 mice breast cancer models, 69 exhibited potent tumor growth inhibition and anti-metastasis effect. Compound 69 as a potent antitumor agent targeting the Hsp90 C-terminal is worthy of further pre-clinical study.