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


Hao JJijun , Ao A Ada , Zhou L Li , Murphy CK Clare K , Frist AY Audrey Y , Keel JJ Jessica J , Thorne CA Curtis A , Kim K Kwangho , Lee E Ethan , Hong CC Charles C . Cell Reports. 2013 9 12; 4(5). 898-904


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 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.