Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery

George M Burslem; Craig M Crews

doi:10.1016/j.cell.2019.11.031

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.

Authors

George M Burslem¹, Craig M Crews²

Affiliations

¹ Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.
² Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA; Departments of Chemistry and Pharmacology, Yale University, New Haven, CT, USA. Electronic address: craig.crews@yale.edu.

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

Grants and funding

R35 CA197589/CA/NCI NIH HHS/United States