Deubiquitinase-targeting chimeras (DUBTACs): a game-changing approach for targeted protein stabilization in drug discovery

Targeted protein degradation (TPD) has transformed drug discovery by enabling event-driven elimination of pathogenic proteins, but many diseases arise from protein insufficiency and require restoration rather than removal. Deubiquitinase (DUB)-targeting chimeras (DUBTACs) offer a complementary proximity-pharmacology approach for targeted protein stabilization (TPS), recruiting DUBs to remove degradative ubiquitin chains and prevent proteasomal turnover. These heterobifunctional molecules link a protein-binding ligand to a DUB recruiter, enabling functional rescue. Notably, DUBTACs provide opportunities to stabilize proteins previously considered undruggable. Here, we summarize design principles, emerging applications, and translational challenges and outline priorities for advancing DUBTACs toward therapeutic development.