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.