The rise and rise of protein degradation: Opportunities and challenges ahead

Abstract

The transformational mechanism of action underpinning targeted protein degradation strategies, including proteolysis-targeting chimeras (PROTACs), gives potential for potent in vivo pharmacology and has allowed projects to move rapidly to the clinic. Despite this remarkable progress, there remain many opportunities to improve current, first-generation approaches even further. Our expanding knowledge will allow discovery of new degrading mechanisms with potential to address several limitations of current approaches, including improving scope and efficiency of degradation, improving drug-like properties of degraders, and reducing potential for the emergence of acquired resistance. Here, we discuss potential routes to realize these advances to expand TPD utility even further.

Keywords: Cereblon; Drug discovery; Drug resistance; E3 ligase; IAP; Molecular glue; PROTAC; Targeted protein degradation; VHL.