Progress in the controllability technology of PROTAC

Proteolysis-targeting chimaera (PROTAC) technology functions by directly targeting proteins and catalysing their degradation through an event-driven mode of action, a novel mechanism with significant clinical application prospects for various diseases. Currently, the most advanced PROTAC drug is undergoing phase III clinical trials (NCT05654623). Although PROTACs exhibit significant advantages over traditional small-molecule inhibitors, their catalytic degradation of normal cellular proteins can potentially cause toxic side effects. Therefore, to achieve targeted release of PROTACs and minimize adverse reactions, researchers are actively exploring diverse controllable PROTACs. In this review, we comprehensively summarize the control strategies to provide a theoretical basis for the innovative application of PROTAC technology. [Display omitted] •Traditional PROTACs might lead to serious side effects.•Development of controllable PROTACs can minimize the on-target off-tissue toxicity.•Design of different types of controllable PROTAC accelerates technological innovation.