Design and delivery of targeting chimeras therapeutics in managing central nervous system disorders

Abstracts: Site-specific degradation by targeting chimeras (TACs) has become a desirable alternative to occupancy-driven inhibition for central nervous system (CNS) diseases due to the possibility of completely de-activating pathogenic proteins, rather than being a complete blocking. The catalytic mechanism of targeting chimeras is dynamic, meaning that they can provide sustained therapeutic effects at low doses in clearing key pathogenic proteins associated with central nervous system diseases, while resisting the development of resistance mechanisms. However, the physicochemical properties of targeting chimeras pose a high delivery question for the brain, limiting brain bioavailability and impairing clinical progress. limiting their brain bioavailability, and hindering clinical progress. To address this issue, this review presents the structure-function relations of targeting chimera modules, focusing on their therapeutic potential in various central nervous system diseases such as glioblastoma, Alzheimer's disease, and Parkinson's disease, as well as the role of novel nanocarriers and delivery platforms in overcoming biological barriers. The review is intended to inform future brain-penetrant targeting chimera therapeutics.