Strategy and Design of In Situ Activated Protein Hydrolysis Targeted Chimeras

Protein hydrolysis targeted chimeras (PROTACs) represent a different therapeutic approach, particularly relevant for overcoming challenges associated with traditional small molecule inhibitors. These challenges include targeting difficult proteins that are often deemed "undruggable" and addressing issues of acquired resistance. PROTACs employ the body's own E3 ubiquitin ligases to induce the degradation of specific proteins of interest (POIs) through the ubiquitin-proteasome pathway. This process is cyclical, allowing for broad applicability, potent protein degradation, and selective targeting. Despite their effectiveness, PROTACs can inadvertently target and degrade nonspecific proteins, potentially resulting in significant side effects and off-target toxicity. To address this concern, researchers have created stimuli-activated PROTACs that enhance targeted protein degradation while minimizing potential harm to healthy cells. These advanced PROTACs aim to improve the precision of degradation in both time and space. This article reviews the strategies for in situ activated PROTACs, highlighting key compounds and research advancements associated with various mechanisms of action. The insights presented here aim to guide further exploration in the field of activated PROTACs.