Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery

Cell. 2020 Apr 2;181(1):102-114. doi: 10.1016/j.cell.2019.11.031. Epub 2020 Jan 16.

Abstract

New biological tools provide new techniques to probe fundamental biological processes. Here we describe the burgeoning field of proteolysis-targeting chimeras (PROTACs), which are capable of modulating protein concentrations at a post-translational level by co-opting the ubiquitin-proteasome system. We describe the PROTAC technology and its application to drug discovery and provide examples where PROTACs have enabled novel biological insights. Furthermore, we provide a workflow for PROTAC development and use and discuss the benefits and issues associated with PROTACs. Finally, we compare PROTAC-mediated protein-level modulation with other technologies, such as RNAi and genome editing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Drug Discovery*
  • Humans
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteolysis*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex