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

Amir Ata Saei; Hjalmar Gullberg; Pierre Sabatier; Christian M Beusch; Katarina Johansson; Bo Lundgren; Per I Arvidsson; Elias S J Arnér; Roman A Zubarev

doi:10.1016/j.redox.2020.101491

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

Redox Biol. 2020 May:32:101491. doi: 10.1016/j.redox.2020.101491. Epub 2020 Mar 3.

Authors

Amir Ata Saei¹, Hjalmar Gullberg², Pierre Sabatier³, Christian M Beusch³, Katarina Johansson⁴, Bo Lundgren², Per I Arvidsson⁵, Elias S J Arnér², Roman A Zubarev⁶

Affiliations

¹ 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.
² 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.
³ Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65, Stockholm, Sweden.
⁴ Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 65, Stockholm, Sweden; Pfizer Innovations AB, 191 90, Sollentuna, Sweden.
⁵ 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.
⁶ 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.

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.

Keywords: Ligand; Mechanism of action; Melting temperature; Protein expression; Target.

Publication types

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

MeSH terms

Auranofin* / pharmacology
Oxidation-Reduction
Pharmaceutical Preparations*
Proteomics
Thioredoxin Reductase 1 / metabolism

Substances

Pharmaceutical Preparations
Auranofin
Thioredoxin Reductase 1