Unraveling the secrets of novel PROTACs to improve degradation efficacy.

Proteolysis targeting chimera (PROTAC) represents a crucial approach for overcoming various limitations associated with traditional inhibitors, particularly in targeting "undruggable" proteins and overcoming the resistance of targets. The degradation efficiency of PROTAC is fundamental to its pharmacological activity. Improving PROTAC's degradation efficiency mainly focuses on small molecule design, exploring new mechanisms, and optimizing delivery strategies. However, there is a lack of comprehensive understanding regarding how novel PROTACs enhance degradation efficacy. Here, a comprehensive exploration of novel PROTACs has been conducted to reveal the mechanisms of enhanced degradation efficiency through an in-depth analysis of tremendous existing studies. Firstly, we describe the variables influencing PROTAC's degradation activity. Secondly, a complete analysis is launched between novel PROTACs and their traditional counterparts, elucidating the reasons for the improved degradation efficacy of newer forms. Finally, the successful cases are leveraged to verify the theoretical foundation underlying enhanced degradation efficacy. We believe this work is anticipated to offer new perspectives for the design and guide the creation of potent PROTACs.