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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-05-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231720302433 |
| _version_ | 1819020246371008512 |
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| author | Amir Ata Saei Hjalmar Gullberg Pierre Sabatier Christian M. Beusch Katarina Johansson Bo Lundgren Per I. Arvidsson Elias S.J. Arnér Roman A. Zubarev |
| author_facet | Amir Ata Saei Hjalmar Gullberg Pierre Sabatier Christian M. Beusch Katarina Johansson Bo Lundgren Per I. Arvidsson Elias S.J. Arnér Roman A. Zubarev |
| author_sort | Amir Ata Saei |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T03:48:09Z |
| format | Article |
| id | doaj.art-66852d1ff08741ec855db8d5f4ff457f |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-21T03:48:09Z |
| publishDate | 2020-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-66852d1ff08741ec855db8d5f4ff457f2022-12-21T19:17:02ZengElsevierRedox Biology2213-23172020-05-0132Comprehensive chemical proteomics for target deconvolution of the redox active drug auranofinAmir Ata Saei0Hjalmar Gullberg1Pierre Sabatier2Christian M. Beusch3Katarina Johansson4Bo Lundgren5Per I. Arvidsson6Elias S.J. Arnér7Roman A. Zubarev8Division 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, SwedenScience for Life Laboratory, Drug Discovery and Development Platform, Biochemical and Cellular Assay Facility, Stockholm, Sweden and Department of Biochemistry and Biophysics, Stockholm University, Stockholm, SwedenDivision of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65, Stockholm, SwedenDivision of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65, Stockholm, SwedenDivision of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 65, Stockholm, Sweden; Pfizer Innovations AB, 191 90, Sollentuna, SwedenScience for Life Laboratory, Drug Discovery and Development Platform, Biochemical and Cellular Assay Facility, Stockholm, Sweden and Department of Biochemistry and Biophysics, Stockholm University, Stockholm, SwedenScience 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, SwedenScience for Life Laboratory, Drug Discovery and Development Platform, Biochemical and Cellular Assay Facility, Stockholm, Sweden and Department of Biochemistry and Biophysics, Stockholm University, Stockholm, SwedenDivision 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; Corresponding author. Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65, Stockholm, Sweden.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.http://www.sciencedirect.com/science/article/pii/S2213231720302433LigandMechanism of actionProtein expressionMelting temperatureTarget |
| spellingShingle | Amir Ata Saei Hjalmar Gullberg Pierre Sabatier Christian M. Beusch Katarina Johansson Bo Lundgren Per I. Arvidsson Elias S.J. Arnér Roman A. Zubarev Comprehensive chemical proteomics for target deconvolution of the redox active drug auranofin Redox Biology Ligand Mechanism of action Protein expression Melting temperature Target |
| title | Comprehensive chemical proteomics for target deconvolution of the redox active drug auranofin |
| title_full | Comprehensive chemical proteomics for target deconvolution of the redox active drug auranofin |
| title_fullStr | Comprehensive chemical proteomics for target deconvolution of the redox active drug auranofin |
| title_full_unstemmed | Comprehensive chemical proteomics for target deconvolution of the redox active drug auranofin |
| title_short | Comprehensive chemical proteomics for target deconvolution of the redox active drug auranofin |
| title_sort | comprehensive chemical proteomics for target deconvolution of the redox active drug auranofin |
| topic | Ligand Mechanism of action Protein expression Melting temperature Target |
| url | http://www.sciencedirect.com/science/article/pii/S2213231720302433 |
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