MST and TRIC Technology to Reliably Study PROTAC Binary and Ternary Binding in Drug Development

Tanja Bartoschik, Andreas Zoephel, Klaus Rumpel, Alessio Ciulli, Charles Heffern (Lead / Corresponding author)

Research output: Chapter in Book/Report/Conference proceedingChapter (peer-reviewed)peer-review

Abstract

PROTACs have shown promise as a new class of therapy, with a unique mechanism of action orthogonal to traditional small molecules that are used to regulate protein activity. Their novel MOA utilizing the body's natural protein degradation machinery degrades a protein of interest rather than inhibiting its function. This strategy has several advantages over conventional small-molecule inhibitors, e.g., higher sensitivity, less off-target effects, and greater target space. However, unlocking the potential of PROTACs necessitates drug discovery techniques that can support the complexity of the novel MOA. In this chapter, we describe the application of MicroScale Thermophoresis (MST) and Temperature-Related Intensity Change (TRIC) to characterize both the binary and ternary binding of PROTACs with target proteins and ubiquitin ligases along with an efficient determination of the cooperativity of the ternary complex formation. The assay development and experimental procedure to characterize the well-described BET PROTAC MZ1 show how MST and TRIC can be applied as a fast and highly sensitive method for PROTAC discovery.

Original languageEnglish
Title of host publicationTargeted Protein Degradation
Subtitle of host publicationMethods and Protocols
EditorsAngela M. Cacace, Christopher M. Hickey, Miklós Békés
Place of PublicationNew York
PublisherHumana Press
Pages115-133
Number of pages19
Edition1
ISBN (Electronic)9781071616659
ISBN (Print)9781071616642 (hbk), 9781071616673 (pbk)
DOIs
Publication statusPublished - 2021

Publication series

NameMethods in Molecular Biology
Volume2365
ISSN (Print)1064-3745
ISSN (Electronic)1940-6029

Keywords

  • MST
  • MicroScale Thermophoresis
  • PROTAC
  • TRIC
  • Temperature-related intensity change

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