Frontiers in PROTACs

Gregory R Hughes; Ashley P Dudey; Andrew M Hemmings; Andrew Chantry

doi:10.1016/j.drudis.2021.04.010

Frontiers in PROTACs

Drug Discov Today. 2021 Oct;26(10):2377-2383. doi: 10.1016/j.drudis.2021.04.010. Epub 2021 Apr 17.

Authors

Gregory R Hughes¹, Ashley P Dudey², Andrew M Hemmings³, Andrew Chantry⁴

Affiliations

¹ School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK; Department of Chemistry, King's College London, SE1 1DB, UK.
² School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK.
³ School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK; School of Chemistry, University of East Anglia, Norwich NR4 7TJ, UK.
⁴ School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK. Electronic address: a.chantry@uea.ac.uk.

PMID: 33872800
DOI: 10.1016/j.drudis.2021.04.010

Abstract

Targeting protein-protein interactions (PPI) is a key focus in the development of new and emerging small-molecule therapeutics. Shallow interacting surfaces can render PPI targeting notoriously difficult. This leaves many therapeutically captivating targets 'undruggable'. Despite these challenges, there has been extraordinary progress circumventing this issue by hijacking the ubiquitin proteasome system (UPS) to target selected substrates for destruction using target-based degradation (TBD) strategies, including bifunctional molecules known as proteolysis-targeting chimeras (PROTACs). In this review, we discuss some of the most recent innovative concepts emerging from PROTAC research and related technologies.

Keywords: Drug discovery; PROTACs; Ubiquitin ligases.

Publication types

Review

MeSH terms

Drug Development / methods*
Drug Discovery / methods
Humans
Molecular Targeted Therapy*
Proteasome Endopeptidase Complex / metabolism
Proteins / metabolism*
Proteolysis

Substances

Proteins
Proteasome Endopeptidase Complex