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Comprehensive chemical proteomics for target deconvolution of the redox active drug auranofin.
Redox Biol. 2020 05; 32:101491.RB

Abstract

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.

Authors+Show Affiliations

Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65, Stockholm, Sweden; Science for Life Laboratory, Drug Discovery and Development Platform, Biochemical and Cellular Assay Facility, Stockholm, Sweden and Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.Science for Life Laboratory, Drug Discovery and Development Platform, Biochemical and Cellular Assay Facility, Stockholm, Sweden and Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65, Stockholm, Sweden.Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65, Stockholm, Sweden.Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 65, Stockholm, Sweden; Pfizer Innovations AB, 191 90, Sollentuna, Sweden.Science for Life Laboratory, Drug Discovery and Development Platform, Biochemical and Cellular Assay Facility, Stockholm, Sweden and Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.Science for Life Laboratory Drug Discovery and Development Platform and Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65, Stockholm, Sweden.Science for Life Laboratory, Drug Discovery and Development Platform, Biochemical and Cellular Assay Facility, Stockholm, Sweden and Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65, Stockholm, Sweden; Sechenov First Moscow State Medical University, 119146, Moscow, Russia. Electronic address: Roman.Zubarev@ki.se.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32199331

Citation

Saei, Amir Ata, et al. "Comprehensive Chemical Proteomics for Target Deconvolution of the Redox Active Drug Auranofin." Redox Biology, vol. 32, 2020, p. 101491.
Saei AA, Gullberg H, Sabatier P, et al. Comprehensive chemical proteomics for target deconvolution of the redox active drug auranofin. Redox Biol. 2020;32:101491.
Saei, A. A., Gullberg, H., Sabatier, P., Beusch, C. M., Johansson, K., Lundgren, B., Arvidsson, P. I., Arnér, E. S. J., & Zubarev, R. A. (2020). Comprehensive chemical proteomics for target deconvolution of the redox active drug auranofin. Redox Biology, 32, 101491. https://doi.org/10.1016/j.redox.2020.101491
Saei AA, et al. Comprehensive Chemical Proteomics for Target Deconvolution of the Redox Active Drug Auranofin. Redox Biol. 2020;32:101491. PubMed PMID: 32199331.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comprehensive chemical proteomics for target deconvolution of the redox active drug auranofin. AU - Saei,Amir Ata, AU - Gullberg,Hjalmar, AU - Sabatier,Pierre, AU - Beusch,Christian M, AU - Johansson,Katarina, AU - Lundgren,Bo, AU - Arvidsson,Per I, AU - Arnér,Elias S J, AU - Zubarev,Roman A, Y1 - 2020/03/03/ PY - 2020/02/12/received PY - 2020/02/17/revised PY - 2020/03/02/accepted PY - 2020/3/22/pubmed PY - 2020/3/22/medline PY - 2020/3/22/entrez KW - Ligand KW - Mechanism of action KW - Melting temperature KW - Protein expression KW - Target SP - 101491 EP - 101491 JF - Redox biology JO - Redox Biol VL - 32 N2 - 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. SN - 2213-2317 UR - https://www.unboundmedicine.com/medline/citation/32199331/Comprehensive_chemical_proteomics_for_target_deconvolution_of_the_redox_active_drug_auranofin L2 - https://linkinghub.elsevier.com/retrieve/pii/S2213-2317(20)30243-3 DB - PRIME DP - Unbound Medicine ER -
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