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Assays and technologies for developing proteolysis targeting chimera degraders.

Authors
  • Liu, Xingui1
  • Zhang, Xuan2
  • Lv, Dongwen1
  • Yuan, Yaxia1
  • Zheng, Guangrong2
  • Zhou, Daohong1
  • 1 Department of Pharmacodynamics, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL 32610, USA.
  • 2 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL 32610, USA.
Type
Published Article
Journal
Future Medicinal Chemistry
Publisher
"Future Science, LTD"
Publication Date
Jun 01, 2020
Volume
12
Issue
12
Pages
1155–1179
Identifiers
DOI: 10.4155/fmc-2020-0073
PMID: 32431173
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Targeted protein degradation by small-molecule degraders represents an emerging mode of action in drug discovery. Proteolysis targeting chimeras (PROTACs) are small molecules that can recruit an E3 ligase and a protein of interest (POI) into proximity, leading to induced ubiquitination and degradation of the POI by the proteasome system. To date, the design and optimization of PROTACs remain empirical due to the complicated mechanism of induced protein degradation. Nevertheless, it is increasingly appreciated that profiling step-by-step along the ubiquitin-proteasome degradation pathway using biochemical and biophysical assays are essential in understanding the structure-activity relationship and facilitating the rational design of PROTACs. This review aims to summarize these assays and to discuss the potential of expanding the toolbox with other new techniques.

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