Identification Of Small Molecule TRABID Deubiquitinase Inhibitors By Computation-Based Virtual Screen
Tong Shi1, Ju Bao2, Nick X Wang2
1Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA.
BMC Chemical Biology
|May 16, 2012
Summary
Researchers investigated TRABID
Area of Science:
- Molecular Biology
- Biochemistry
- Cancer Research
Background:
- Wnt/β-catenin signaling is crucial in biological processes and tumorigenesis.
- Elevated β-catenin transcription activity is common in cancer.
- TRABID, a deubiquitinase, was previously suggested to enhance Wnt/β-catenin transcription, indicating potential as an anti-cancer target.
Purpose of the Study:
- To investigate the role of TRABID in Wnt/β-catenin-mediated gene transcription.
- To identify small molecule inhibitors of TRABID's deubiquitinase (DUB) activity.
- To assess the impact of TRABID inhibition or modulation on Wnt/β-catenin signaling.
Main Methods:
- Structure-based virtual screening to identify TRABID inhibitors.
- In vitro deubiquitinase (DUB) assays to confirm inhibitor activity.
- Gene transcription assays using TRABID shRNAs, wildtype TRABID, and DUB-deficient mutants.
Main Results:
- Several small molecules inhibiting TRABID DUB activity were identified.
- These TRABID inhibitors did not affect β-catenin-mediated gene transcription.
- Modulating TRABID expression (shRNA, wildtype, or mutant) had minimal impact on Wnt/β-catenin transcription.
Conclusions:
- TRABID may not be essential for canonical Wnt/β-catenin signal transduction.
- A small amount of TRABID might be sufficient for its regulatory role in Wnt activity.
- TRABID's role in Wnt/β-catenin signaling and its potential as an anti-cancer target require further investigation.
