Stimuli‐Responsive PROTACs for Controlled Protein Degradation

Abstract Proteolysis Targeting Chimeras (PROTACs) represent a promising therapeutic modality to address undruggable and resistant issues in drug discovery. However, potential on‐target toxicity remains clinically challenging. We developed a generalized caging strategy to synthesize a series of stimuli‐responsive PROTACs (sr‐PROTACs) with diverse molecular blocks bearing robust and cleavable linkers, presenting “turn on” features in manipulating protein degradation. By leveraging pathological cues, such as elevated ROS, phosphatase, H 2 S, or hypoxia, and external triggers, such as ultraviolet light, X‐Ray, or bioorthogonal reagents, we achieved site‐specific activation and traceless release of original PROTACs through de‐caging and subsequent self‐immolative cleavage, realizing selective uptake and controlled protein degradation in vitro. An in vivo study revealed that two sr‐PROTACs with phosphate‐ and fluorine‐containing cages exhibited high solubility and long plasma exposure, which were specifically activated by tumor overexpressing phosphatase or low dosage of X‐Ray irradiation in situ, leading to efficient protein degradation and potent tumor remission. With more reactive biomarkers to be screened from clinical practice, our caging library could provide a general tool to design activatable PROTACs, prodrugs, antibody‐drug conjugates, and smart biomaterials for personalized treatment, tissue engineering or regenerative medicine.