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- W4385655668 abstract "Hsp90α is an isoform of the heat shock protein 90 (Hsp90) family of molecular chaperones and mediates the folding and activation of ∼400 client proteins. However, inhibition of intracellular Hsp90α has caused detrimental side effects and significantly hindered the clinical development of Hsp90 inhibitors. As an alternative strategy, 14 Hsp90α-selective inhibitors were synthesized to introduce permanently charged moieties onto the solvent-exposed portion of the Hsp90α binding site to produce cell-impermeable extracellular Hsp90α-selective inhibitors. The resulting lead compounds were cell-permeable dimethylamine 14 (NDNA3), with an affinity of 0.51 μM for Hsp90α and >196-fold selectivity over the other Hsp90 isoforms, and cell-impermeable quaternary ammonium 17 (NDNA4), with an affinity of 0.34 μM for Hsp90α and >294-fold selectivity. The permanently charged analogs were determined to have low membrane permeability, to be nontoxic against Ovcar-8 and MCF-10A cells, to avoid disruption of hERG channel maturation, and not to induce the heat shock response or Hsp90α-dependent client degradation." @default.
- W4385655668 created "2023-08-09" @default.
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- W4385655668 date "2023-08-08" @default.
- W4385655668 modified "2023-09-24" @default.
- W4385655668 title "Synthesis and Validation of the First Cell-Impermeable Hsp90α-Selective Inhibitors" @default.
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- W4385655668 doi "https://doi.org/10.1021/acsmedchemlett.3c00265" @default.
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