Selective Small Molecule Targeting β-Catenin Function Discovered by In Vivo Chemical Genetic Screen

• Discovery of windorphen (WD), a Wnt inhibitor, in an in vivo chemical screen
• WD functionally targets zebrafish β-catenin-1, required for ventral development
• WD inhibits p300 histone acetyltransferase, disrupting β-catenin:p300 interaction
• WD robustly kills cancer cells that have aberrant Wnt signaling

SummaryThe 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 in vivo 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.

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