Smart PROTACs Enable Controllable Protein Degradation for Precision Cancer Therapy

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional chemicals that degrade proteins at the post-translational level, which represent an emerging therapeutic modality to fight cancer and other diseases. Although several PROTACs have now entered clinical trials, potential off-tissue side effects have resulted from nonspecific accumulation at non-cancerous sites after systemic administration, and this remains a major challenge. To this end, in the past 3 years, activatable PROTACs whose activity can only be launched on demand have gained tremendous momentum. In this review, we provide an overview of these new smart activatable PROTACs, which exert protein degradation action only in response to internal or external stimuli. We categorize these activatable PROTACs according to their activation mechanism contributed by different stimuli, including reduction-activatable, hypoxia-activatable, and enzyme-activatable PROTACs and photo-caged or photo-switchable PROTACs. The use of stimuli-responsive chemical blocks in these activatable PROTACs allows local activation of the antitumor effects while reducing the incidence of off-site side effects for precision cancer therapy. The design principle and category of smart PROTACs are introduced along with an overview of their therapeutic prospects and challenges.