Structure-based discovery of a novel inhibitor targeting the β-catenin/Tcf4 interaction

Biochemistry. 2012 Jan 17;51(2):724-31. doi: 10.1021/bi201428h. Epub 2012 Jan 6.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / chemistry
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Crystallography, X-Ray
  • Down-Regulation / drug effects
  • Drug Evaluation, Preclinical / methods*
  • HCT116 Cells
  • Humans
  • Models, Molecular
  • Protein Binding / drug effects
  • Protein Conformation
  • Small Molecule Libraries / pharmacology*
  • Transcription Factor 4
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism*
  • Transcription, Genetic / drug effects
  • User-Computer Interface
  • Wnt Signaling Pathway / drug effects
  • Wnt Signaling Pathway / genetics
  • beta Catenin / chemistry
  • beta Catenin / genetics
  • beta Catenin / metabolism*


  • Antineoplastic Agents
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Basic Helix-Loop-Helix Transcription Factors
  • Small Molecule Libraries
  • TCF3 protein, human
  • TCF4 protein, human
  • Transcription Factor 4
  • Transcription Factors
  • beta Catenin