Native Mass Spectrometry for the Study of PROTAC GNE-987-Containing Ternary Complexes.
ChemMedChem
; 16(14): 2206-2210, 2021 07 20.
Article
em En
| MEDLINE
| ID: mdl-33792163
ABSTRACT
PROteolysis TArgeting Chimeras (PROTACs) promote the degradation, rather than inhibition, of a drug target as a mechanism for therapeutic treatment. Bifunctional PROTAC molecules allow simultaneous binding of both the target protein and an E3-Ubiquitin ligase, bringing the two proteins into close spatial proximity to allow ubiquitinylation and degradation of the target protein via the cell's endogenous protein degradation pathway. We utilized native mass spectrometry (MS) to study the ternary complexes promoted by the previously reported PROTAC GNE-987 between Brd4 bromodomains 1 and 2, and Von Hippel Lindeau E3-Ubiquitin Ligase. Native MS at high resolution allowed us to measure ternary complex formation as a function of PROTAC concentration to provide a measure of complex affinity and stability, whilst simultaneously measuring other intermediate protein species. Native MS provides a high-throughput, low sample consumption, direct screening method to measure ternary complexes for PROTAC development.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
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Proteínas de Ciclo Celular
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Ubiquitina-Proteína Ligases
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Amidas
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article