Abstract
Overactivation or overexpression of β-catenin in the Wnt (wingless) signaling pathway plays an important role in tumorigenesis. Interaction of β-catenin with T-cell factor (Tcf) DNA binding proteins is a key step in the activation of the proliferative genes in response to upstream signals of this Wnt/β-catenin pathway. Recently, we identified a new small molecule inhibitor, named BC21 (C(32)H(36)Cl(2)Cu(2)N(2)O(2)), which effectively inhibits the binding of β-catenin with Tcf4-derived peptide and suppresses β-catenin/Tcf4 driven reporter gene activity. This inhibitor decreases the viability of β-catenin overexpressing HCT116 colon cancer cells that harbor the β-catenin mutation, and more significantly, it inhibits the clonogenic activity of these cells. Down-regulation of c-Myc and cyclin D1 expression, the two important effectors of the Wnt/β-catenin signaling, is confirmed by treating HCT116 cells with BC21. This compound represents a new and modifiable potential anticancer candidate that targets β-catenin/Tcf-4 interaction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / chemistry
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Crystallography, X-Ray
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Down-Regulation / drug effects
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Drug Evaluation, Preclinical / methods*
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HCT116 Cells
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Humans
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Models, Molecular
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Protein Binding / drug effects
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Protein Conformation
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Small Molecule Libraries / pharmacology*
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Transcription Factor 4
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Transcription Factors / chemistry
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Transcription Factors / metabolism*
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Transcription, Genetic / drug effects
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User-Computer Interface
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Wnt Signaling Pathway / drug effects
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Wnt Signaling Pathway / genetics
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beta Catenin / chemistry
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beta Catenin / genetics
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beta Catenin / metabolism*
Substances
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Antineoplastic Agents
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Basic Helix-Loop-Helix Transcription Factors
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Small Molecule Libraries
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TCF3 protein, human
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TCF4 protein, human
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Transcription Factor 4
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Transcription Factors
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beta Catenin