Abstract
A series of amides of ethacrynic acid was prepared and evaluated for their ability to inhibit Wnt signaling and decrease the survival of CLL cells. Several of the most potent derivatives were active in the low micromolar range. Reduction of the alpha,beta-unsaturated carbon-carbon double bond of EA abrogated both the inhibition of Wnt signaling as well as the decrease in CLL survival. Preliminary mechanism of action studies suggest that these derivatives covalently modify sulfhydryl groups present on transcription factors important for Wnt/beta-catenin signaling.
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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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Carbon / chemistry
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Cell Line, Tumor
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Cell Survival / drug effects*
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Chemistry, Pharmaceutical / methods*
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Dose-Response Relationship, Drug
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Drug Design
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Drug Screening Assays, Antitumor
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Ethacrynic Acid / analogs & derivatives*
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Ethacrynic Acid / chemistry
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Humans
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Inhibitory Concentration 50
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Models, Chemical
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Signal Transduction
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Wnt Proteins / antagonists & inhibitors*
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beta Catenin / antagonists & inhibitors*
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beta Catenin / metabolism
Substances
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Antineoplastic Agents
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Wnt Proteins
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beta Catenin
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Carbon
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Ethacrynic Acid