Abstract
Glucose regulated protein 94 kDa, Grp94, is the endoplasmic reticulum (ER) localized isoform of heat shock protein 90 (Hsp90) that is responsible for the trafficking and maturation of toll-like receptors, immunoglobulins, and integrins. As a result, Grp94 has emerged as a therapeutic target to disrupt cellular communication, adhesion, and tumor proliferation, potentially with fewer side effects compared to pan-inhibitors of all Hsp90 isoforms. Although, the N-terminal ATP binding site is highly conserved among all four Hsp90 isoforms, recent cocrystal structures of Grp94 have revealed subtle differences between Grp94 and other Hsp90 isoforms that has been exploited for the development of Grp94-selective inhibitors. In the current study, a structure-based approach has been applied to a Grp94 nonselective compound, SNX 2112, which led to the development of 8j (ACO1), a Grp94-selective inhibitor that manifests ∼440 nM affinity and >200-fold selectivity against cytosolic Hsp90 isoforms.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Benzoquinones / pharmacology
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Binding Sites
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Cell Line, Tumor
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Cell Movement / drug effects
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Cytoskeletal Proteins / chemistry
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Cytoskeletal Proteins / genetics
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Eye Proteins / chemistry
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Eye Proteins / genetics
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Glycoproteins / chemistry
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Glycoproteins / genetics
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / chemistry
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Heterocyclic Compounds, 4 or More Rings / chemistry
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Heterocyclic Compounds, 4 or More Rings / pharmacology
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Humans
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Lactams, Macrocyclic / pharmacology
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Membrane Glycoproteins / antagonists & inhibitors*
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Membrane Glycoproteins / chemistry
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Models, Molecular
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Molecular Conformation
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / chemistry
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Structure-Activity Relationship
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ortho-Aminobenzoates / chemical synthesis
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ortho-Aminobenzoates / chemistry
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ortho-Aminobenzoates / pharmacology*
Substances
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4-(2-(2-hydroxybenzyl)-1H-pyrrol-1-yl)-2-((4-hydroxycyclohexyl)amino)benzamide
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Antineoplastic Agents
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Benzoquinones
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Cytoskeletal Proteins
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Eye Proteins
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Glycoproteins
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HSP90 Heat-Shock Proteins
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Heterocyclic Compounds, 4 or More Rings
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Lactams, Macrocyclic
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Membrane Glycoproteins
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Protein Isoforms
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SNX 2112
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endoplasmin
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ortho-Aminobenzoates
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trabecular meshwork-induced glucocorticoid response protein
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tanespimycin