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Nat Rev Drug Discov. 2019 Dec;18(12):949-963. doi: 10.1038/s41573-019-0047-y. Epub 2019 Oct 30.

Targeted protein degradation: expanding the toolbox.

Author information

1
Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada. matthieu.schapira@utoronto.ca.
2
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. matthieu.schapira@utoronto.ca.
3
Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA.
4
Structural Genomics Consortium, University of Oxford, Oxford, UK.
5
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, USA.
6
Department of Chemistry, Yale University, New Haven, CT, USA.
7
Department of Pharmacology, Yale University, New Haven, CT, USA.

Abstract

Proteolysis-targeting chimeras (PROTACs) and related molecules that induce targeted protein degradation by the ubiquitin-proteasome system represent a new therapeutic modality and are the focus of great interest, owing to potential advantages over traditional occupancy-based inhibitors with respect to dosing, side effects, drug resistance and modulating 'undruggable' targets. However, the technology is still maturing, and the design elements for successful PROTAC-based drugs are currently being elucidated. Importantly, fewer than 10 of the more than 600 E3 ubiquitin ligases have so far been exploited for targeted protein degradation, and expansion of knowledge in this area is a key opportunity. Here, we briefly discuss lessons learned about targeted protein degradation in chemical biology and drug discovery and systematically review the expression profile, domain architecture and chemical tractability of human E3 ligases that could expand the toolbox for PROTAC discovery.

PMID:
31666732
DOI:
10.1038/s41573-019-0047-y

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