Research Progress of Proteolysis-Targeting Chimera Technology and Its Linkers in Cancer Therapy.

Proteolysis-targeting chimera (PROTAC) is a bifunctional molecule technology that utilizes the ubiquitin-proteasome system to selectively degrade target proteins. Compared to traditional drugs, it demonstrates significant potential in overcoming drug resistance, targeting "undruggable" targets, and reducing off-target toxicity. The degradation efficiency of PROTAC is closely related to its molecular design, with optimization of the linker significantly enhancing its efficacy. This review will summarize the working principles of PROTAC, focusing on the impact of linker length, flexibility, and cleavability on its function, and outline targeting strategies based on linker engineering.