The Vital Role of Proteomics in Characterizing Novel Protein Degraders
| Autor: | Göran Dahl, Katelyn Cassidy, Kevin Moreau, Andrew X. Zhang, Fiona Pachl, Andrea M. Zuhl |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Proteomics
0301 basic medicine Proteasome Endopeptidase Complex Computer science Ubiquitin-Protein Ligases Computational biology Protein degradation Ligands Biochemistry Mass Spectrometry Analytical Chemistry Small Molecule Libraries 03 medical and health sciences 0302 clinical medicine Drug Discovery Humans Molecular Targeted Therapy Novel protein Mechanism (biology) Ubiquitination Protein turnover High-Throughput Screening Assays Targeted proteomics Eukaryotic Cells 030104 developmental biology 030220 oncology & carcinogenesis Proteolysis Molecular Medicine Protein Processing Post-Translational Protein Binding Biotechnology |
| Zdroj: | SLAS Discovery. 26:518-523 |
| ISSN: | 2472-5552 |
| DOI: | 10.1177/2472555220985776 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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