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

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 inh...

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Published inMethods in molecular biology (Clifton, N.J.) Vol. 2365; p. 115
Main Authors Bartoschik, Tanja, Zoephel, Andreas, Rumpel, Klaus, Ciulli, Alessio, Heffern, Charles
Format Journal Article
LanguageEnglish
Published United States 2021
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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.
AbstractList 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.
Author Zoephel, Andreas
Heffern, Charles
Ciulli, Alessio
Bartoschik, Tanja
Rumpel, Klaus
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  fullname: Heffern, Charles
  email: charles.heffern@nanotempertech.com
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CitedBy_id crossref_primary_10_3390_ijms23147672
crossref_primary_10_1016_j_isci_2023_107919
crossref_primary_10_1016_j_trac_2024_117716
crossref_primary_10_1002_cbic_202300163
crossref_primary_10_1016_j_antiviral_2022_105480
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Keywords MicroScale Thermophoresis
Temperature-related intensity change
PROTAC
MST
TRIC
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Snippet 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...
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SubjectTerms Drug Development
Intercellular Signaling Peptides and Proteins
Proteolysis
Technology
Temperature
Ubiquitin-Protein Ligases - metabolism
Title MST and TRIC Technology to Reliably Study PROTAC Binary and Ternary Binding in Drug Development
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