ArticleACS chemical biology2018
Trifunctional High-Throughput Screen Identifies Promising Scaffold To Inhibit Grp94 and Treat Myocilin-Associated Glaucoma.
Article in ACS chemical biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 30 citations in OpenAlex.
- Ligand-mediated conformation diversity of Hsp90 revealed by GaMD simulations and Markov model.Molecular diversity · 2026Article
- Design, synthesis, and biological properties exhibited by 1,2,3-triazole based Grp94-selective inhibitors.European journal of medicinal chemistry · 2026Article
- Glucose-regulated protein 94 (Grp94/gp96) in viral pathogenesis: Insights into its role and therapeutic potentials.European journal of medicinal chemistry · 2025Review
- Engineered Age-Mimetic Breast Cancer Models Reveal Differential Drug Responses in Young and Aged Microenvironments.Advanced healthcare materials · 2025Article
- Structural basis for anomalous cellular trafficking behavior of glaucoma-associated A427T mutant myocilin.bioRxiv : the preprint server for biology · 2025Article
- Article
- Structural transitions modulate the chaperone activities of Grp94.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Construction of miRNA-mRNA regulatory network indicates potential biomarkers for primary open-angle glaucoma.BMC medical genomics · 2023Article
- Myocilin misfolding and glaucoma: A 20-year update.Progress in retinal and eye research · 2023Review
- Mendelian inheritance revisited: dominance and recessiveness in medical genetics.Nature reviews. Genetics · 2023Review
- Elevated Intraocular Pressure and Glaucomatous Optic Neuropathy: Genes to Disease Mechanisms, Therapeutic Drugs, and Gene Therapies.Pharmaceuticals (Basel, Switzerland) · 2023Review
- The biology and inhibition of glucose-regulated protein 94/gp96.Medicinal research reviews · 2022Review
- Amyloid fibrillation of the glaucoma associated myocilin protein is inhibited by epicatechin gallate (ECG).RSC advances · 2022Article
- Common and rare myocilin variants: Predicting glaucoma pathogenicity based on genetics, clinical, and laboratory misfolding data.Human mutation · 2021Review
- Molecular Insights into Myocilin and Its Glaucoma-Causing Misfolded Olfactomedin Domain Variants.Accounts of chemical research · 2021Review
- Myocilin-associated Glaucoma: A Historical Perspective and Recent Research Progress.Molecular vision · 2021Review
- Different Grp94 components interact transiently with the myocilin olfactomedin domain in vitro to enhance or retard its amyloid aggregation.Scientific reports · 2019Article
- Stable calcium-free myocilin olfactomedin domain variants reveal challenges in differentiating between benign and glaucoma-causing mutations.The Journal of biological chemistry · 2019Article
- Physiological function of myocilin and its role in the pathogenesis of glaucoma in the trabecular meshwork (Review).International journal of molecular medicine · 2019Review
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.