Abstract
The modulation of gene regulation by blocking the interaction between the thyroid receptor (TR) and obligate coregulators has been reported recently with the discovery of the lead compound 3-(dimethylamino)-1-(4-hexylphenyl)propan-1-one). Herein we report studies aimed at optimization of this initial hit to determine the basic parameters of the structure-activity relationships and clarify the mechanism of action. These studies provided new insights, showing that activity and TRbeta isoform selectivity is highly correlated with the structural composition of these covalent inhibitors.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acrylamides / chemical synthesis
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Acrylamides / pharmacology
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Acrylamides / toxicity
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Acrylates / chemical synthesis
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Acrylates / pharmacology
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Acrylates / toxicity
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Binding, Competitive
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Cell Line, Tumor
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Cell Survival / drug effects
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Humans
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Ketones / chemical synthesis*
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Ketones / pharmacology
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Ketones / toxicity
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Membranes, Artificial
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Models, Molecular
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Nuclear Receptor Coactivator 2 / metabolism*
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Peptides / metabolism
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Permeability
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Protein Isoforms / metabolism
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Solubility
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Stereoisomerism
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Structure-Activity Relationship
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Thyroid Hormone Receptors alpha / metabolism*
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Thyroid Hormone Receptors beta / metabolism*
Substances
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Acrylamides
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Acrylates
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Ketones
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Membranes, Artificial
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Nuclear Receptor Coactivator 2
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Peptides
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Protein Isoforms
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Thyroid Hormone Receptors alpha
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Thyroid Hormone Receptors beta