AUTHOR=Kuemper Sandra , Cairns Andrew G. , Birchall Kristian , Yao Zhi , Large Jonathan M. TITLE=Targeted protein degradation in CNS disorders: a promising route to novel therapeutics? JOURNAL=Frontiers in Molecular Neuroscience VOLUME=17 YEAR=2024 URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2024.1370509 DOI=10.3389/fnmol.2024.1370509 ISSN=1662-5099 ABSTRACT=

Targeted protein degradation (TPD) is a rapidly expanding field, with various PROTACs (proteolysis-targeting chimeras) in clinical trials and molecular glues such as immunomodulatory imide drugs (IMiDs) already well established in the treatment of certain blood cancers. Many current approaches are focused on oncology targets, leaving numerous potential applications underexplored. Targeting proteins for degradation offers a novel therapeutic route for targets whose inhibition remains challenging, such as protein aggregates in neurodegenerative diseases. This mini review focuses on the prospect of utilizing TPD for neurodegenerative disease targets, particularly PROTAC and molecular glue formats and opportunities for novel CNS E3 ligases. Some key challenges of utilizing such modalities including molecular design of degrader molecules, drug delivery and blood brain barrier penetrance will be discussed.