Structure-based discovery of a novel inhibitor targeting the β-catenin/Tcf4 interaction.
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.
Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York 13210, United States.
Wang
W
Tian
Xiaofeng
X
Han
Maocai
M
Yan
Yan
Y
Xu
Srinivas
S
Duggineni
Nan
N
Lin
Guifen
G
Luo
Yan Michael
YM
Li
Xiaobing
X
Han
Ziwei
Z
Huang
Jing
J
An
D000970:Antineoplastic Agents / Q000494:pharmacology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D045325:HCT116 Cells; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D054852:Small Molecule Libraries / Q000494:pharmacology*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014584:User-Computer Interface; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics; D051176:beta Catenin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D054852:Small Molecule Libraries; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin; C407909:TCF3 protein, human; C532096:TCF4 protein, human