ZFIN ID: ZDB-PUB-130911-9
Selective Small Molecule Targeting β-Catenin Function Discovered by In Vivo Chemical Genetic Screen
Hao, J., Ao, A., Zhou, L., Murphy, C.K., Frist, A.Y., Keel, J.J., Thorne, C.A., Kim, K., Lee, E., and Hong, C.C.
Date: 2013
Source: Cell Reports   4(5): 898-904 (Journal)
Registered Authors: Hong, Charles
Keywords: none
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents/pharmacology
  • Apoptosis/drug effects
  • Cell Line, Tumor
  • Colonic Neoplasms/drug therapy
  • Colonic Neoplasms/metabolism
  • Colonic Neoplasms/pathology
  • Enzyme Inhibitors/pharmacology
  • Humans
  • Molecular Sequence Data
  • Molecular Targeted Therapy
  • Mutation
  • Wnt Proteins/antagonists & inhibitors*
  • Wnt Proteins/metabolism
  • Wnt Signaling Pathway/drug effects
  • Zebrafish
  • beta Catenin/antagonists & inhibitors*
  • beta Catenin/metabolism
  • p300-CBP Transcription Factors/antagonists & inhibitors
  • p300-CBP Transcription Factors/metabolism
PubMed: 24012757 Full text @ Cell Rep.

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.