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Published on: November 9, 2020
Expanding the targeted protein degradation approach with small molecule chimeras directed to the 26S proteasome
Mireia Casasampere1, Hector Carneros1, Tania Roda1
1Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18, Barcelona, Spain.
Abstract:
Classical proteolysis targeting chimeras (Protacs) bind specific targets and E3 ubiquitin-ligases, promoting ubiquitination and degradation of targets by the proteasome. Multiple chimeras that degrade proteins relevant in several diseases have been developed, and the number is quickly increasing, indicating their therapeutic projection. Given the specificities of proteolytic pathways and limitations in E3-based Protacs, alternative strategies in targeted protein degradation are pursued. Herein, using two targets relevant in oncology as models (IMPDH2 and CERT1), we provide proof of concept for 26S-oriented compounds based on small-molecule ligands of USP14, a 26S-associated deubiquitinase involved in substrate processing and allosteric regulation of 26S activity. Our findings will expand the potential of targeted protein degradation.
Insights
New proteolysis targeting chimeras (Protacs) offer a novel strategy for targeted protein degradation by targeting the 26S proteasome. This approach utilizes small molecules to modulate deubiquitinase activity, expanding therapeutic potential.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Proteolysis targeting chimeras (Protacs) are emerging therapeutics that hijack the ubiquitin-proteasome system to degrade target proteins.
- Current Protacs rely on E3 ligase recruitment, facing limitations due to pathway specificities.
- Targeted protein degradation is a rapidly advancing field with significant therapeutic promise.
Purpose of the Study:
- To explore alternative strategies for targeted protein degradation beyond E3 ligase-based Protacs.
- To provide proof of concept for 26S-oriented compounds targeting the deubiquitinase USP14.
- To investigate the potential of modulating 26S proteasome activity for therapeutic protein degradation.
Main Methods:
- Utilized IMPDH2 and CERT1 as model targets relevant in oncology.
- Developed small-molecule ligands targeting USP14, a deubiquitinase associated with the 26S proteasome.
- Investigated the mechanism of 26S-oriented compounds in protein degradation.
Main Results:
- Demonstrated proof of concept for 26S-oriented compounds.
- Showcased the role of USP14 in substrate processing and allosteric regulation of 26S activity.
- Identified a novel approach to targeted protein degradation.
Conclusions:
- 26S-oriented compounds represent a promising alternative strategy for targeted protein degradation.
- Modulating USP14 activity offers a new avenue for therapeutic intervention.
- These findings expand the scope and potential of targeted protein degradation therapies.
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