Deubiquitinase-Targeting Chimeras (DUBTACs) as a Potential Paradigm-Shifting Drug Discovery Approach

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.