Selective small molecule targeting β-catenin function discovered by in vivo chemical genetic screen

Jijun Hao, Ada Ao, Li Zhou, Clare K. Murphy, Audrey Y. Frist, Jessica J. Keel, Curtis A. Thorne, Kwangho Kim, Ethan Lee, Charles C. Hong

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

The canonical Wnt signaling pathway, mediated by the transcription factor β-catenin, plays critical roles in embryonic development and represents an important therapeutic target. In a zebrafish-based invivo screen for small molecules that specifically perturb embryonic dorsoventral patterning, we discovered a compound named windorphen that selectively blocks the Wnt signal required for ventral development. Windorphen exhibits remarkable specificity toward β-catenin-1 function, indicating that the two β-catenin isoforms found in zebrafish are not functionally redundant. We show that windorphen is a selective inhibitor of p300 histone acetyltransferase, a coactivator that associates with β-catenin. Finally, windorphen robustly and selectively kills cancer cells that harbor Wnt-activating mutations, supporting the therapeutic potential of this Wnt inhibitor class

Original languageEnglish (US)
Pages (from-to)898-904
Number of pages7
JournalCell Reports
Volume4
Issue number5
DOIs
StatePublished - May 12 2013
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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