Deubiquitinase-Targeting Chimeras (DUBTACs) as a Potential Paradigm-Shifting Drug Discovery Approach
Zonghui Ma1, Mingxiang Zhou1, Haiying Chen1
1Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States.
Abstract:
Developing proteolysis-targeting chimeras (PROTACs) is well recognized through target protein degradation (TPD) toward promising therapeutics. While a variety of diseases are driven by aberrant ubiquitination and degradation of critical proteins with protective functions, target protein stabilization (TPS) rather than TPD is emerging as a unique therapeutic modality. Deubiquitinase-targeting chimeras (DUBTACs), a class of heterobifunctional protein stabilizers consisting of deubiquitinase (DUB) and protein-of-interest (POI) targeting ligands conjugated with a linker, can rescue such proteins from aberrant elimination. DUBTACs stabilize the levels of POIs in a DUB-dependent manner, removing ubiquitin from polyubiquitylated and degraded proteins. DUBTACs can induce a new interaction between POI and DUB by forming a POI-DUBTAC-DUB ternary complex. Herein, therapeutic benefits of TPS approaches for human diseases are introduced, and recent advances in developing DUBTACs are summarized. Relevant challenges, opportunities, and future perspectives are also discussed.
Insights
Deubiquitinase-targeting chimeras (DUBTACs) offer a novel therapeutic strategy by stabilizing proteins, unlike traditional target protein degradation (TPD) methods. These compounds rescue essential proteins from degradation, presenting new treatment opportunities for various diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Target protein degradation (TPD) using proteolysis-targeting chimeras (PROTACs) is a recognized therapeutic approach.
- Aberrant protein degradation underlies various diseases, creating a need for alternative therapeutic strategies.
- Target protein stabilization (TPS) emerges as a promising modality to counteract disease-causing protein loss.
Purpose of the Study:
- Introduce the therapeutic benefits of target protein stabilization (TPS) for human diseases.
- Summarize recent advances in the development of deubiquitinase-targeting chimeras (DUBTACs).
- Discuss challenges, opportunities, and future perspectives in DUBTAC development.
Main Methods:
- DUBTACs are heterobifunctional molecules linking deubiquitinase (DUB) and protein-of-interest (POI) targeting ligands.
- DUBTACs induce ternary complex formation (POI-DUBTAC-DUB) to stabilize target proteins.
- Mechanism involves removing ubiquitin from proteins targeted for degradation.
Main Results:
- DUBTACs demonstrate the ability to stabilize target proteins in a deubiquitinase-dependent manner.
- This stabilization rescues proteins from aberrant elimination, counteracting disease mechanisms.
- DUBTACs represent a viable strategy for therapeutic intervention by modulating protein levels.
Conclusions:
- Deubiquitinase-targeting chimeras (DUBTACs) offer a unique therapeutic approach through target protein stabilization (TPS).
- DUBTACs can counteract diseases driven by the loss of protective proteins.
- Further research into DUBTACs holds significant promise for future therapeutic applications.
