Direct Targeting of β-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/β-Catenin Signaling

So-Young Hwang; Xianming Deng; Sanguine Byun; Chan Lee; Seung-Joo Lee; Hyunsuk Suh; Jianming Zhang; Qiaofeng Kang; Ting Zhang; Kenneth D Westover; Anna Mandinova; Sam W Lee

doi:10.1016/j.celrep.2016.05.071

Direct Targeting of β-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/β-Catenin Signaling

Cell Rep. 2016 Jun 28;16(1):28-36. doi: 10.1016/j.celrep.2016.05.071. Epub 2016 Jun 16.

Authors

Affiliations

¹ Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
² State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
³ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Biochemistry and Radiation Oncology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
⁵ Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: [email protected].
⁶ Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: [email protected].

Abstract

The Wnt/β-catenin signaling pathway plays a major role in tissue homeostasis, and its dysregulation can lead to various human diseases. Aberrant activation of β-catenin is oncogenic and is a critical driver in the development and progression of human cancers. Despite the significant potential of targeting the oncogenic β-catenin pathway for cancer therapy, the development of specific inhibitors remains insufficient. Using a T cell factor (TCF)-dependent luciferase-reporter system, we screened for small-molecule compounds that act against Wnt/β-catenin signaling and identified MSAB (methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate) as a selective inhibitor of Wnt/β-catenin signaling. MSAB shows potent anti-tumor effects selectively on Wnt-dependent cancer cells in vitro and in mouse cancer models. MSAB binds to β-catenin, promoting its degradation, and specifically downregulates Wnt/β-catenin target genes. Our findings might represent an effective therapeutic strategy for cancers addicted to the Wnt/β-catenin signaling pathway.

MeSH terms

Animals
Benzoates / chemistry
Benzoates / pharmacology*
Cell Line, Tumor
Mice
Oncogenes*
Proteasome Endopeptidase Complex / metabolism*
Proteolysis / drug effects*
Small Molecule Libraries / pharmacology*
Sulfonamides / chemistry
Sulfonamides / pharmacology*
Wnt Signaling Pathway / drug effects*
Xenograft Model Antitumor Assays
beta Catenin / metabolism*
meta-Aminobenzoates / chemistry
meta-Aminobenzoates / pharmacology*

Substances

Benzoates
Small Molecule Libraries
Sulfonamides
beta Catenin
meta-Aminobenzoates
methyl 3-(((4-methylphenyl)sulfonyl)amino)benzoate
Proteasome Endopeptidase Complex

Abstract

MeSH terms

Substances

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