PROTACs for central nervous system disorders: challenges and opportunities

Central nervous system (CNS) disorders, particularly neurodegenerative diseases and brain tumors, pose substantial and long-standing challenges to the global public health system. Current therapeutic approaches for CNS disorders are primarily confined to symptomatic relief and generally fail to halt or reverse disease progression. However, proteolysis-targeting chimeras (PROTACs), as an emerging therapeutic strategy, have introduced new prospects for effective intervention in this domain. Although several studies have demonstrated the use of PROTACs in degrading pathogenic proteins associated with CNS disorders, their clinical translation remains hindered by multiple challenges, including insufficient degradation efficiency, potential off-target toxicity, and limited blood-brain barrier (BBB) permeability. In response to the above challenges, researchers are actively pursuing various strategies-ranging from structural optimization of PROTACs to enhance their degradative activity, to the implementation of novel nano-delivery systems and targeted delivery approaches to improve BBB permeability and tissue selectivity. These strategic advancements have demonstrated significant potential in preclinical research for the treatment of CNS disorders. This review provides a comprehensive overview of the research and development of various PROTACs targeting CNS disorders, and highlights potential application strategies for advancing protein degrader therapeutics in the CNS field. By synthesizing current advances and challenges, it offers researchers in related disciplines a well-defined theoretical framework and forward-looking strategic guidance, thereby facilitating in-depth investigation and transformative applications in this rapidly evolving domain.