The rise and rise of protein degradation: Opportunities and challenges ahead. Issue 12 (December 2021)

• Record Type: Journal Article
• Authors: Hughes, Scott J.; Testa, Andrea; Thompson, Nicola; Churcher, Ian
• Is Part Of: Drug discovery today. Volume 26:Issue 12(2021)
• Page Start: 2889
• Page End: 2897
• Publication Date: 2021-12
• Subjects: Targeted protein degradation -- PROTAC -- E3 ligase -- Drug discovery -- Cereblon -- VHL -- IAP -- Drug resistance -- Molecular glue; Drugs -- Design -- Periodicals; Drugs -- Research -- Periodicals; 615.1
• DOI: 10.1016/j.drudis.2021.08.006
• Languages: English
• ISSNs: 1359-6446

Abstract

Highlights: Many PROTACs now in clinic but many opportunities for further improvements remain. New degrading mechanisms needed to overcome limitations of existing TPD approaches. New TPD mechanisms allow discovery of new degrading warheads with improved properties. New TPD mechanisms will give increased scope and reduced potential for tumor resistance. 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.