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Development and characterisation of SMURF2-targeting modifiers
Dhanoop Manikoth Ayyathan1, Gal Levy-Cohen1, Moran Shubely2
1Laboratory of Molecular and Cellular Cancer Biology, Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
Journal of Enzyme Inhibition and Medicinal Chemistry
|January 12, 2021
Summary
Researchers developed synthetic molecules to target the SMURF2 E3 ubiquitin ligase, promoting its degradation. This approach accelerates cell growth and enhances sensitivity to chemotherapy drugs like etoposide.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- SMURF2, a C2-WW-HECT-domain E3 ubiquitin ligase, regulates key cellular functions.
- No specific modulators for SMURF2 have been previously developed.
Purpose of the Study:
- To design and evaluate synthetic peptides and peptidomimetics targeting SMURF2.
- To investigate SMURF2 modulation via disruption of intramolecular C2-HECT domain interactions.
- To assess the impact of SMURF2 targeting on cellular processes and drug sensitivity.
Main Methods:
- Generation and screening of SMURF2-targeting synthetic peptides and peptidomimetics.
- In vitro and in cellulo assays to determine molecular effects.
- Utilisation of SMURF2-specific shRNAs for comparative analysis.
- Assessment of cell growth and cytotoxicity in combination treatments.
Main Results:
- Developed SMURF2 modulators effective at nanomolar concentrations.
- Demonstrated that SMURF2 targeting accelerates cell growth in a context-dependent manner.
- Showed that SMURF2 inactivation potentiates etoposide-induced cytotoxicity.
Conclusions:
- SMURF2 is druggable through induction of its autoubiquitination and turnover.
- Targeting SMURF2 offers a potential strategy to enhance anticancer drug efficacy.
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