ArticleJournal of medicinal chemistry2018
Structure Based Design of a Grp94-Selective Inhibitor: Exploiting a Key Residue in Grp94 To Optimize Paralog-Selective Binding.
Article in Journal of medicinal chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 43 citations in OpenAlex.
- Ligand-mediated conformation diversity of Hsp90 revealed by GaMD simulations and Markov model.Molecular diversity · 2026Article
- Attempts to Achieve Targeted Covalent Inhibition of Hsp90β.Chemical biology & drug design · 2026Article
- Optimization of an Hsp90β-selective inhibitor via exploration of the Hsp90 N-terminal ATP-binding pocket.European journal of medicinal chemistry · 2025Article
- A Novel Small-Molecule GRP94 Modulator Increases PCSK9 Secretion and Promotes LDLR Degradation.Life (Basel, Switzerland) · 2025Article
- Glucose-regulated protein 94 (Grp94/gp96) in viral pathogenesis: Insights into its role and therapeutic potentials.European journal of medicinal chemistry · 2025Review
- Characterization and Inhibition of the Chaperone Function of Plasmodium falciparum Glucose-Regulated Protein 94 kDa (Pf Grp94).Proteins · 2025Article
- The structural and functional dynamics of BiP and Grp94: opportunities for therapeutic discovery.Trends in pharmacological sciences · 2025Review
- Advances in the structures, mechanisms and targeting of molecular chaperones.Signal transduction and targeted therapy · 2025Review
- Selective Inhibition of hsp90 Paralogs: Uncovering the Role of Helix 1 in Grp94-Selective Ligand Binding.Proteins · 2025Article
- Heat shock proteins as hallmarks of cancer: insights from molecular mechanisms to therapeutic strategies.Journal of hematology & oncology · 2024Review
- Selective inhibition of hsp90 paralogs: Uncovering the role of helix 1 in Grp94-selective ligand binding.bioRxiv : the preprint server for biology · 2024Article
- Tracing genetic diversity captures the molecular basis of misfolding disease.Nature communications · 2024Article
- Visualization of conformational transition of GRP94 in solution.Life science alliance · 2024Article
- Enniatin A Analogues as Novel Hsp90 Inhibitors that Modulate Triple-Negative Breast Cancer.ACS medicinal chemistry letters · 2023Article
- Pharmacophore Model-Based Virtual Screening Workflow for Discovery of Inhibitors TargetingACS omega · 2023Article
- Pan-HSP90 ligand binding reveals isoform-specific differences in plasticity and water networks.Protein science : a publication of the Protein Society · 2023Article
- The biology and inhibition of glucose-regulated protein 94/gp96.Medicinal research reviews · 2022Review
- A campaign targeting a conserved Hsp70 binding site uncovers how subcellular localization is linked to distinct biological activities.Cell chemical biology · 2022Article
- Crystal structure of the middle and C-terminal domains of Hsp90α labeled with a coumarin derivative reveals a potential allosteric binding site as a drug target.Acta crystallographica. Section D, Structural biology · 2022Article
- Inhibitors of theCells · 2021Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Grp94 and Hsp90, the ER and cytoplasmic hsp90 paralogs, share a conserved ATP-binding pocket that has been targeted for therapeutics. Paralog-selective inhibitors may lead to drugs with fewer side effects. Here, we analyzed 1 (BnIm), a benzyl imidazole resorcinylic inhibitor, for its mode of binding. The structures of 1 bound to Hsp90 and Grp94 reveal large conformational changes in Grp94 but not Hsp90 that expose site 2, a binding pocket adjacent to the central ATP cavity that is ordinarily blocked. The Grp94:1 structure reveals a flipped pose of the resorcinylic scaffold that inserts into the exposed site 2. We exploited this flipped binding pose to develop a Grp94-selective derivative of 1. Our structural analysis shows that the ability of the ligand to insert its benzyl imidazole substituent into site 1, a different side pocket off the ATP binding cavity, is the key to exposing site 2 in 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.