Precise Modulation of Protein Degradation by Smart PROTACs

Abstract Proteolysis‐targeting chimera (PROTAC) has emerged as an attractive therapeutic modality in drug discovery. PROTACs are bifunctional molecules that effectively bridge proteins of interest (POIs) with E3 ubiquitin ligases, such that, the target proteins are tagged with ubiquitin and subsequently degraded via the proteasome. Despite significant progress in the field of targeted protein degradation (TPD), the application of conventional PROTAC degraders still faces significant challenges, including systemic toxicity induced by non‐tissue‐specific targeting. To address this issue, a variety of smart PROTACs that can be activated by specific stimuli, have been developed for achieving conditional and spatiotemporal modulation of protein levels. Here, on the basis of our contributions, we overview recent advances of smart PROTACs, including tumor microenvironment‐, photo‐, and X‐ray radiation‐responsive PROTACs, that enable controllable TPD. The design strategy, case studies, potential applications and challenges will be focused on.