Assays and technologies for developing proteolysis targeting chimera degraders

Xingui Liu, Xuan Zhang, Dongwen Lv, Yaxia Yuan, Guangrong Zheng, Daohong Zhou

Research output: Contribution to journalReview articlepeer-review

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1155-1179
Number of pages25
JournalFuture Medicinal Chemistry
Volume12
Issue number12
DOIs
StatePublished - Jun 2020
Externally publishedYes

Keywords

  • PROTAC
  • biochemical assay
  • biophysical assay
  • degraders
  • protein degradation
  • protein ubiquitination
  • ternary complex

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

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