Abstract
Recent progress in the development of inhibitors of protein-protein interactions has opened the door for developing drugs that act by novel and selective mechanisms. Building on that work, we designed a small-molecule inhibitor of the Wnt signaling pathway, which is aberrantly activated across a wide range of human tumors. The compound, named FJ9, disrupts the interaction between the Frizzed-7 Wnt receptor and the PDZ domain of Dishevelled, down-regulating canonical Wnt signaling and suppressing tumor cell growth. The antitumorigenic effects of FJ9 were pronounced, including induction of apoptosis in human cancer cell lines and tumor growth inhibition in a mouse xenograft model. FJ9 is thus among the first non-peptide inhibitors to show therapeutic efficacy through disruption of PDZ protein-protein interactions.
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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Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Apoptosis / drug effects
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Cell Growth Processes / drug effects
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Cell Growth Processes / physiology
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Cell Line, Tumor
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Dishevelled Proteins
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Female
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Frizzled Receptors / antagonists & inhibitors
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Frizzled Receptors / metabolism
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HCT116 Cells
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HeLa Cells
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Humans
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Indoles / pharmacology*
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Mice
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Mice, Nude
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Models, Molecular
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Phosphoproteins / antagonists & inhibitors*
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Phosphoproteins / metabolism
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Protein Structure, Tertiary
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Receptors, G-Protein-Coupled / antagonists & inhibitors
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Receptors, G-Protein-Coupled / metabolism
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Signal Transduction / drug effects
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Wnt Proteins / antagonists & inhibitors
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Wnt Proteins / metabolism
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Xenograft Model Antitumor Assays
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beta Catenin / antagonists & inhibitors*
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beta Catenin / physiology
Substances
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Adaptor Proteins, Signal Transducing
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Dishevelled Proteins
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FJ9 compound
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FZD7 protein, human
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Frizzled Receptors
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Indoles
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Phosphoproteins
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Receptors, G-Protein-Coupled
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Wnt Proteins
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beta Catenin