The Vital Role of Proteomics in Characterizing Novel Protein Degraders.
SLAS Discov
; 26(4): 518-523, 2021 04.
Article
em En
| MEDLINE
| ID: mdl-33615886
ABSTRACT
Mass spectrometry-based proteomics profiling is a discovery tool that enables researchers to understand the mechanisms of action of drug candidates. When applied to proteolysis targeting chimeras (PROTACs) such approaches provide unbiased perspectives of the binding, degradation selectivity, and mechanism related to efficacy and safety. Specifically, global profiling experiments can identify direct degradation events and assess downstream pathway modulation that may result from degradation or off-target inhibition. Targeted proteomics approaches can be used to quantify the levels of relevant E3 ligases and the protein of interest in cell lines and tissues of interest, which can inform the line of sight and provide insights on possible safety liabilities early in the project. Furthermore, proteomics approaches can be applied to understand protein turnover and resynthesis rates and inform on target tractability, as well as pharmacokinetics/pharmacodynamics understanding. In this perspective, we survey the literature around the impact of mass spectrometry-based proteomics in the development of PROTACs and present our envisioned proteomics cascade for supporting targeted protein degradation projects.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Processamento de Proteína Pós-Traducional
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Ubiquitina-Proteína Ligases
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Complexo de Endopeptidases do Proteassoma
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Bibliotecas de Moléculas Pequenas
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Ensaios de Triagem em Larga Escala
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Terapia de Alvo Molecular
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article