The application of ubiquitin ligases in the PROTAC drug design.

Protein ubiquitylation plays important roles in many biological activities. Protein ubiquitylation is a unique process that is mainly controlled by ubiquitin ligases. The ubiquitin-proteasome system (UPS) is the main process to degrade short-lived and unwanted proteins in eukaryotes. Many components in the UPS are attractive drug targets. Recent studies indicated that ubiquitin ligases can be employed as tools in proteolysis-targeting chimeras (PROTACs) for drug discovery. In this review article, we will discuss the recent progress of the application of ubiquitin ligases in the PROTAC drug design. We will also discuss advantages and existing problems of PROTACs. Moreover, we will propose a few principles for selecting ubiquitin ligases in PROTAC applications.