Intermolecular interaction-based ubiquitin-proteasome system-targeting drug discovery

Abstract

We review recent advances of Ubiquitin-Proteasome System (UPS)-based research and development with increased focus as drug discovery approaches and introduce applications of chimera-type small molecule compounds (SNIPER/PROTAC) that selectively promote degradation of a drug target protein. UPS makes the point (polyubiquitin chain) of targeting protein as a substrate and has a property that degrade the target protein with proteasome. Protein knockout technologies degrade the drug target protein by apply this protein degrading system. In current technologies, polyubiquitin chains are artificially added to the drug target proteins through small molecules and introduce degradation of the target proteins. The approaches are divided into 2 types, one of which is E3 modulator-based technology represented by thalidomide, the other one is chimera compound-based technology represented by SNIPER/PROTAC. Furthermore, novel technologies are practically used to identify small molecule E3 binders as well as E3-targeting protein binders. These new approaches are expected to contribute to the efficient UPS-based drug discovery.