Designing the Proteome with Chemical Tools: Degrons and Beyond

Cell biology relies on precise changes in protein stability, which can be chemically harnessed to transform cell fate. Decades of research have revealed the many intricate systems underlying cellular proteostasis, which can be hijacked by proximity‐based degrader compounds. The archetypal degrader, PROteolysis TArgeting Chimera (PROTAC), recruits E3 ligases to protein targets to facilitate their ubiquitination and degradation in the proteasome. Being able to customize the human proteome with chemical tools has great value for fundamental research and for clinical progress through the controlled elimination of disease‐causing proteins. Success within the degrader field has reinvigorated interest in mapping the mechanisms underlying native protein degradation, which has platformed new degrader classes capable of advancing the field towards the goal of degrading the entire human proteome. This review discusses ongoing strategies to identify degrons regulating native protein turnover, advances in chemical tools to activate these degrons, and new attempts to streamline degron pathways for simplified targeted protein degradation. The continued discovery and application of degrons has the power to transform human biology and combat disease.