Abstract
We disclose the first small molecule histone deacetylase (HDAC) inhibitor (3, BRD73954) capable of potently and selectively inhibiting both HDAC6 and HDAC8 despite the fact that these isoforms belong to distinct phylogenetic classes within the HDAC family of enzymes. Our data demonstrate that meta substituents of phenyl hydroxamic acids are readily accommodated upon binding to HDAC6 and, furthermore, are necessary for the potent inhibition of HDAC8.
Publication types
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Research Support, Non-U.S. Gov't
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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HeLa Cells
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Histone Deacetylase 6
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Histone Deacetylase Inhibitors / chemical synthesis*
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Histone Deacetylase Inhibitors / chemistry
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Histone Deacetylase Inhibitors / pharmacology
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Histone Deacetylases / chemistry
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Histone Deacetylases / metabolism*
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Humans
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Hydroxamic Acids / chemical synthesis*
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacology
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Molecular Docking Simulation
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Phthalic Acids / chemical synthesis*
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Phthalic Acids / chemistry
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Phthalic Acids / pharmacology
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Protein Binding
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Repressor Proteins / antagonists & inhibitors*
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Repressor Proteins / chemistry
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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BRD73954
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Phthalic Acids
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Repressor Proteins
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HDAC6 protein, human
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HDAC8 protein, human
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Histone Deacetylase 6
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Histone Deacetylases