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

Hao J, Ao A, Zhou L, Murphy CK, Frist AY, Keel JJ, Thorne CA, Kim K, Lee E, Hong CC
Cell Rep. 2013 4 (5): 898-904

PMID: 24012757 · PMCID: PMC3923627 · DOI:10.1016/j.celrep.2013.07.047

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.

Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

MeSH Terms (16)

Amino Acid Sequence Animals Antineoplastic Agents Apoptosis beta Catenin Cell Line, Tumor Colonic Neoplasms Enzyme Inhibitors Humans Molecular Sequence Data Molecular Targeted Therapy Mutation p300-CBP Transcription Factors Wnt Proteins Wnt Signaling Pathway Zebrafish

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