6ASQ

Structure of Grp94 bound to methyl 2-[2-(2-benzylpyridin-3-yl)ethyl]-3-chloro-4,6-dihydroxybenzoate, a pan-Hsp90 inhibitor

Summary for 6ASQ

• Entry DOI: 10.2210/pdb6asq/pdb
• Descriptor: Endoplasmin, 3,6,9,12,15,18,21-HEPTAOXATRICOSANE-1,23-DIOL, DI(HYDROXYETHYL)ETHER, ... (6 entities in total)
• Functional Keywords: grp94, hsp90, inhibitor, chaperone-inhibitor complex, chaperone/inhibitor
• Biological source: Canis lupus familiaris (Dog); More
• Total number of polymer chains: 2
• Total formula weight: 58673.34

Authors

Huard, D.J.E.,Lieberman, R.L. (deposition date: 2017-08-25, release date: 2018-04-18, Last modification date: 2023-10-04)

Primary citation

Huard, D.J.E.,Crowley, V.M.,Du, Y.,Cordova, R.A.,Sun, Z.,Tomlin, M.O.,Dickey, C.A.,Koren, J.,Blair, L.,Fu, H.,Blagg, B.S.J.,Lieberman, R.L.
Trifunctional High-Throughput Screen Identifies Promising Scaffold To Inhibit Grp94 and Treat Myocilin-Associated Glaucoma.
ACS Chem. Biol., 13:933-941, 2018

PubMed Abstract: Gain-of-function mutations within the olfactomedin (OLF) domain of myocilin result in its toxic intracellular accumulation and hasten the onset of open-angle glaucoma. The absence of myocilin does not cause disease; therefore, strategies aimed at eliminating myocilin could lead to a successful glaucoma treatment. The endoplasmic reticulum Hsp90 paralog Grp94 accelerates OLF aggregation. Knockdown or pharmacological inhibition of Grp94 in cells facilitates clearance of mutant myocilin via a non-proteasomal pathway. Here, we expanded our support for targeting Grp94 over cytosolic paralogs Hsp90α and Hsp90β. We then developed a high-throughput screening assay to identify new chemical matter capable of disrupting the Grp94/OLF interaction. When applied to a blind, focused library of 17 Hsp90 inhibitors, our miniaturized single-read in vitro thioflavin T -based kinetics aggregation assay exclusively identified compounds that target the chaperone N-terminal nucleotide binding site. In follow up studies, one compound (2) decreased the extent of co-aggregation of Grp94 with OLF in a dose-dependent manner in vitro, and enabled clearance of the aggregation-prone full-length myocilin variant I477N in cells without inducing the heat shock response or causing cytotoxicity. Comparison of the co-crystal structure of compound 2 and another non-selective hit in complex with the N-terminal domain of Grp94 reveals a docking mode tailored to Grp94 and explains its selectivity. A new lead compound has been identified, supporting a targeted chemical biology assay approach to develop a protein degradation-based therapy for myocilin-associated glaucoma by selectively inhibiting Grp94.

PubMed: 29402077
DOI: 10.1021/acschembio.7b01083

Experimental method

X-RAY DIFFRACTION (2.35 Å)