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Publication Abstract from PubMed

The heat shock protein 90 (Hsp90) family of molecular chaperones regulates protein homeostasis, folding, and degradation. The ER-resident Hsp90 isoform, glucose-regulated protein 94 (Grp94), promotes the aggregation of mutant forms of myocilin, a protein associated with primary open-angle glaucoma. While inhibition of Grp94 promotes the degradation of mutant myocilin in vitro, to date no Grp94-selective inhibitors have been investigated in vivo. Here, a Grp94-selective inhibitor facilitated mutant myocilin degradation and rescued phenotypes in a transgenic mouse model of hereditary primary open-angle glaucoma. Ocular toxicities previously associated with pan-Hsp90 inhibitors were not evident with our Grp94-selective inhibitor, 4-Br-BnIm. Our study suggests that selective inhibition of a distinct Hsp90 family member holds translational promise for ocular and other diseases associated with cell stress and protein misfolding.

Isoform-selective Hsp90 inhibition rescues model of hereditary open-angle glaucoma.,Stothert AR, Suntharalingam A, Tang X, Crowley VM, Mishra SJ, Webster JM, Nordhues BA, Huard DJE, Passaglia CL, Lieberman RL, Blagg BSJ, Blair LJ, Koren J 3rd, Dickey CA Sci Rep. 2017 Dec 20;7(1):17951. doi: 10.1038/s41598-017-18344-4. PMID:29263415^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.