Selective Small Molecule Targeting β-Catenin Function Discovered by In Vivo Chemical Genetic Screen
- Authors
- 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.
- ID
- ZDB-PUB-130911-9
- 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.