Unconventional PROTACs for cancer therapy

Targeted protein degradation, which aims to eliminate dysregulated proteins, has emerged as a promising strategy for conquering challenging therapeutic targets. Proteolysis‐targeting chimera (PROTAC) is a heterobifunctional molecule that utilizes the ubiquitin‐proteasome system to selectively degrade target proteins. Due to its ability to degrade “undruggable” proteins without causing drug resistance, PROTAC has shown great potential in innovative drug development, especially in cancer therapy. However, conventional PROTACs suffer from several limitations, such as limited bioavailability and pharmacokinetics caused by complex structures, limited tumor targeting ability, non‐specific toxicity, and hook effects. Therefore, structural innovation of conventional PROTACs to make them meet the therapeutic demand is essential for unlocking the full potential of PROTACs as a therapeutic tool. Here, we summarize four types of unconventional PROTACs for addressing the above challenges and enhancing cancer therapy efficacy, including PROTACs with unconventional binding ligands, PROTACs with unconventional linkers, pro‐PROTACs, and self‐assembled PROTACs. These optimized designs contribute to the development of PROTACs‐based universal platforms, providing directions for innovative drug developments and expanding the applications of PROTACs in cancer therapy.