at-13387 has been researched along with Colitis--Ulcerative* in 2 studies
2 other study(ies) available for at-13387 and Colitis--Ulcerative
| Article | Year |
|---|---|
Design and synthesis of Grp94 selective inhibitors based on Phe199 induced fit mechanism and their anti-inflammatory effects.
Glucose-regulated protein 94 (Grp94), a member of the Heat shock protein 90 (Hsp90) family, is implicated in many human diseases, including cancer, neurodegeneration, inflammatory, and infectious diseases. Here, we describe our effort to design and develop a new series of Grp94 inhibitors based on Phe199 induced fit mechanism. Using an alkynyl-containing inhibitor as a starting point, we developed compound 4, which showed potent inhibitory activity toward Grp94 in a fluorescence polarization-based assay. With improved physicochemical properties and suitable pharmacokinetic properties, compound 4 was advanced into in vivo bioactivity evaluation. In a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis (UC), compound 4 showed anti-inflammatory property and reduced the levels of pro-inflammatory cytokines (TNF-α and IL-6). Together, these findings provide evidence that this approach may be promising for further Grp94 drug development efforts. Topics: Alkynes; Animals; Anti-Inflammatory Agents; Benzamides; Colitis, Ulcerative; Colon; HCT116 Cells; Humans; Male; Membrane Glycoproteins; Mice, Inbred C57BL; Microsomes, Liver; Molecular Docking Simulation; Molecular Structure; Protein Binding; Structure-Activity Relationship | 2021 |
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 IC Topics: Animals; Anti-Inflammatory Agents; Colitis, Ulcerative; Disease Models, Animal; Drug Discovery; HSP70 Heat-Shock Proteins; Inhibitory Concentration 50; Membrane Proteins; Mice; Structure-Activity Relationship | 2018 |