On‐Demand Activatable PROTACs for Targeted Protein Degradation

ABSTRACT

Targeted protein degradation (TPD) has emerged as a transformative paradigm in the biomedical research. Central to this field are Proteolysis‐targeting chimeras (PROTACs), bifunctional molecules exhibiting immense therapeutic potential, particularly in oncology and autoimmune diseases. By recruiting target proteins to E3 ubiquitin ligases, PROTACs harness the ubiquitin‐proteasome system (UPS) to induce protein degradation. This event‐driven mechanism overcomes the “target occupancy‐driven” limitations of conventional small‐molecule inhibitors, offering novel avenues for tackling undruggable targets. Despite this promise, conventional PROTACs face significant translational challenges, including poor tissue specificity, off‐target toxicity, and insufficient accumulation within the tumor microenvironment. Therefore, the development of on‐demand activatable PROTAC prodrugs, capable of spatiotemporally precise protein degradation, has become a central research focus in this field. This review systematically summarizes the design principles and research progress of three major categories of activatable PROTACs: endogenously activatable PROTACs, exogenously photo‐activatable PROTACs, and bioorthogonally activatable PROTACs. We also compare the merits and limitations of these strategies to foster a deeper understanding of the field and accelerate the clinical advancement of PROTAC‐based therapeutics.