Targeted protein degradation: current and future challenges

Curr Opin Chem Biol. 2020 Jun;56:35-41. doi: 10.1016/j.cbpa.2019.11.012. Epub 2020 Jan 2.

Abstract

Traditional approaches in the development of small-molecule drugs typically aim to inhibit the biochemical activity of functional protein domains. In contrast, targeted protein degradation aims to reduce overall levels of disease-relevant proteins. Mechanistically, this can be achieved via chemical ligands that induce molecular proximity between an E3 ubiquitin ligase and a protein of interest, leading to ubiquitination and degradation of the protein of interest. This paradigm-shifting pharmacology promises to address several limitations inherent to conventional inhibitor design. Most notably, targeted protein degradation has the potential not only to expand the druggable proteome beyond the reach of traditional competitive inhibitors but also to develop therapeutic strategies of unmatched selectivity. This review briefly summarizes key challenges that remain to be addressed to deliver on these promises and to realize the full therapeutic potential of pharmacologic modulation of protein degradation pathways.

Keywords: Chemical biology; E3 ligase; Molecular glues; PROTACs; Targeted protein degradation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Drug Design
  • Enzyme Inhibitors / metabolism*
  • Humans
  • Ligands
  • Molecular Targeted Therapy
  • Peptide Termination Factors / chemistry
  • Peptide Termination Factors / metabolism
  • Protein Binding
  • Proteolysis / drug effects*
  • Proteome / chemistry
  • Proteome / metabolism*
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Enzyme Inhibitors
  • Ligands
  • Peptide Termination Factors
  • Proteome
  • SALL4 protein, human
  • Transcription Factors
  • peptide-chain-release factor 3
  • Ubiquitin-Protein Ligases
  • ZFP91 protein, human