PROTACs: A novel strategy for cancer drug discovery and development

Abstract

Abstract Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: a small molecule that binds to a target protein, an E3 ligase ligand (consisting of an E3 ligase and its small molecule recruiter), and a chemical linker that hooks first two components together. In the past 20 years, we have witnessed advancement of multiple PROTAC degraders into the clinical trials for anticancer therapies. However, one of the major challenges of PROTAC technology is that only very limited number of E3 ligase recruiters are currently available as E3 ligand for targeted protein degradation (TPD), although human genome encodes more than 600 E3 ligases. Thus, there is an urgent need to identify additional effective E3 ligase recruiters for TPD applications. In this review, we summarized the existing RING‐type E3 ubiquitin ligase and their small molecule recruiters that act as effective E3 ligands of PROTAC degraders and their application in anticancer drug discovery. We believe that this review could serve as a reference in future development of efficient E3 ligands of PROTAC technology for cancer drug discovery and development.

Keywords

• E3 ligase ligands
• PROTAC degraders
• targeted therapy