Expansion of Targeted Protein Degradation for Targeting Aggregate-prone Proteins and Mitochondrial Proteins

Targeted protein degradation (TPD), a technology that induces the degradation of a protein of interest (POI) by a chemical degrader, is a major trend in drug discovery research. Proteolysis targeting chimeras (PROTACs) are representative degraders that induce the ubiquitination of a POI, leading to its proteasomal degradation. Following the report of PROTAC efficacy in animals approximately a decade ago, TPD research continues to flourish. Unlike the occupancy-driven mechanism of traditional inhibitors, TPD employs an event-driven mechanism. Consequently, TPD is a highly anticipated technology capable of addressing therapeutic targets previously considered “undruggable.” Against this backdrop, our group is actively pursuing research focused on the targeted degradation of undruggable proteins. This symposium review summarizes our studies. It focuses on two distinct areas: the targeted degradation of aggregation-prone proteins for the development of neurodegenerative disorder treatments, and the targeted degradation of mitochondrial matrix-localized proteins for mitochondria-related diseases.