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

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

  • J Med Chem. 2018 Nov 8;61(21):9513-9533. doi: 10.1021/acs.jmedchem.8b00800.
Fen Jiang 1 2,  An-Ping Guo 1 2,  Jia-Chen Xu 1 2,  Qi-Dong You 1 2,  Xiao-Li Xu 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization , China Pharmaceutical University , Nanjing 210009 , China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy , China Pharmaceutical University , Nanjing 210009 , China.
PMID: 30351001 DOI: 10.1021/acs.jmedchem.8b00800
Abstract

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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