Recent Advances in Pro-PROTAC Development to Address On-Target Off-Tumor Toxicity

Proteolysis-targetingchimera (PROTAC) technology represents anovel and promising modality for targeted protein degradation withtransformative implications for the clinical management of variousdiseases. Despite notable advantages, the possibility of on-targetoff-tumor toxicity in healthy cells represents a critical challengeto clinical applications in cancer treatment. Researchers are currentlyexploring strategies to enhance targeted degradation activity in acell-selective manner to minimize undesirable side effects. In thisPerspective, we highlight innovative approaches for prodrug-basedPROTACs (pro-PROTACs) that facilitate tumor-targeted release. Thedevelopment of such approaches may further expand the range of potentialapplications of PROTAC technology within drug development.