Comprehensive chemical proteomics for target deconvolution of the redox active drug auranofin

Chemical proteomics encompasses novel drug target deconvolution methods in which compound modification is not required. Herein we use Thermal Proteome Profiling, Functional Identification of Target by Expression Proteomics and multiplexed redox proteomics for deconvolution of auranofin targets to ai...

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Bibliographic Details
Published in:Redox biology 2020-05, Vol.32, p.101491-101491, Article 101491
Main Authors: Saei, Amir Ata, Gullberg, Hjalmar, Sabatier, Pierre, Beusch, Christian M., Johansson, Katarina, Lundgren, Bo, Arvidsson, Per I., Arnér, Elias S.J., Zubarev, Roman A.
Format: Article
Language:English
Subjects:
Auranofin - pharmacology
Ligand
Mechanism of action
Medicin och hälsovetenskap
Melting temperature
Oxidation-Reduction
Pharmaceutical Preparations
Protein expression
Proteomics
Research Paper
Target
Thioredoxin Reductase 1 - metabolism
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Summary:Chemical proteomics encompasses novel drug target deconvolution methods in which compound modification is not required. Herein we use Thermal Proteome Profiling, Functional Identification of Target by Expression Proteomics and multiplexed redox proteomics for deconvolution of auranofin targets to aid elucidation of its mechanisms of action. Auranofin (Ridaura®) was approved for treatment of rheumatoid arthritis in 1985. Because several clinical trials are currently ongoing to repurpose auranofin for cancer therapy, comprehensive characterization of its targets and effects in cancer cells is important. Together, our chemical proteomics tools confirmed thioredoxin reductase 1 (TXNRD1, EC:1.8.1.9) as a main auranofin target, with perturbation of oxidoreductase pathways as the top mechanism of drug action. Additional indirect targets included NFKB2 and CHORDC1. Our comprehensive data can be used as a proteomic signature resource for further analyses of the effects of auranofin. Here we also assessed the orthogonality and complementarity of different chemical proteomics methods that can furnish invaluable mechanistic information and thus the approach can facilitate drug discovery efforts in general. [Display omitted]
ISSN:2213-2317
2213-2317
DOI:10.1016/j.redox.2020.101491