Abstract
An HTS screening campaign identified a series of low molecular weight phenols that showed excellent selectivity (>100-fold) for HDAC1/HDAC2 over other Class I and Class II HDACs. Evolution and optimization of this HTS hit series provided HDAC1-selective (SHI-1) compounds with excellent anti-proliferative activity and improved physical properties. Dose-dependent efficacy in a mouse HCT116 xenograft model was demonstrated with a phenylglycine SHI-1 analog.
MeSH terms
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Acetylation
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Amides
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Animals
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Cell Proliferation / drug effects*
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Colonic Neoplasms / drug therapy*
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Colonic Neoplasms / enzymology
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Colonic Neoplasms / pathology
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Dogs
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ERG1 Potassium Channel
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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Ether-A-Go-Go Potassium Channels / metabolism
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Glycine / analogs & derivatives*
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Glycine / chemistry
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Histone Deacetylase 1
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Histone Deacetylase Inhibitors*
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Humans
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Macaca mulatta
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Mice
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Molecular Structure
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Phenylalanine / chemistry*
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Structure-Activity Relationship
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Amides
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ERG1 Potassium Channel
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Enzyme Inhibitors
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Ether-A-Go-Go Potassium Channels
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Histone Deacetylase Inhibitors
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phenylglycine chloride
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Phenylalanine
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HDAC1 protein, human
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Hdac1 protein, mouse
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Histone Deacetylase 1
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Glycine