Abstract
We describe the rational generation of small-molecule agents that suppress tumor cell growth by down-regulating canonical Wnt signaling. We first produced a chemical library of the derivatives of indole-2-ketones and carbinols; we then screened them by using scalable assays of biochemical antagonism of Dishevelled-1 PDZ domain interactions and cell-based assays of Dishevelled-1-driven T-cell factor-mediated transcription. Compounds showing parallel effects in these assays were tested for selective induction of apoptosis in cancer cells. A new compound (24) that met the criteria for high biochemical antagonism, T-cell factor-mediated transcription, and induction of tumor-selective apoptosis was found to significantly suppress the growth of tumor xenografts in mice.
Publication types
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Evaluation Study
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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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Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
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Animals
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Apoptosis / drug effects
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Caspase 3 / metabolism
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Caspase 7 / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dishevelled Proteins
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Down-Regulation / drug effects*
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Enzyme Activation / drug effects
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Female
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Gene Expression Regulation, Neoplastic / drug effects*
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Humans
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Inhibitory Concentration 50
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Mice
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Mice, Nude
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Neoplasms / enzymology
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Neoplasms / genetics
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Neoplasms / pathology*
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Phosphoproteins / antagonists & inhibitors*
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Small Molecule Libraries / analysis
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Small Molecule Libraries / chemical synthesis
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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TCF Transcription Factors / metabolism*
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Transcription, Genetic / drug effects*
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Xenograft Model Antitumor Assays
Substances
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Adaptor Proteins, Signal Transducing
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DVL1 protein, human
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Dishevelled Proteins
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Dvl1 protein, mouse
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Phosphoproteins
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Small Molecule Libraries
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TCF Transcription Factors
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Caspase 3
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Caspase 7