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

ABSTRACT: The canonical Wnt signaling pathway, mediated by the transcription factor ?-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 ?-catenin-1 function, indicating that the two ?-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 ?-catenin. Finally, windorphen robustly and selectively kills cancer cells that harbor Wnt-activating mutations, supporting the therapeutic potential of this Wnt inhibitor class.

SUBMITTER: Hao J

PROVIDER: S-EPMC3923627 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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

Hao Jijun J Ao Ada A Zhou Li L Murphy Clare K CK Frist Audrey Y AY Keel Jessica J JJ Thorne Curtis A CA Kim Kwangho K Lee Ethan E Hong Charles C CC

Cell reports 20130905 5

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 t ...[more]

PMID: 24012757

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