1. Comprehensive chemical proteomics for target deconvolution of the redox active drug auranofin
- Author
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Christian M. Beusch, Hjalmar Gullberg, Katarina Johansson, Bo Lundgren, Amir Ata Saei, Pierre Sabatier, Per I. Arvidsson, Elias S.J. Arnér, and Roman A. Zubarev
- Subjects
Proteomics ,PISA, Proteome Integral Solubility Alteration assay ,0301 basic medicine ,Drug ,Target ,Thioredoxin Reductase 1 ,Auranofin ,FITEXP, Functional Identification of Target by Expression Proteomics ,media_common.quotation_subject ,Clinical Biochemistry ,CETSA, Cellular Thermal Shift Assay ,Ligand ,Computational biology ,Drug action ,Mechanism of action ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Redox active ,Pharmaceutical sciences ,lcsh:QH301-705.5 ,Melting temperature ,media_common ,lcsh:R5-920 ,Chemistry ,Drug discovery ,TPP, Thermal Proteome Profiling ,Organic Chemistry ,030104 developmental biology ,Pharmaceutical Preparations ,lcsh:Biology (General) ,TR-TPP, Temperature Range-Thermal Proteome Profiling ,Protein expression ,Deconvolution ,lcsh:Medicine (General) ,Oxidation-Reduction ,TXNRD1, Thioredoxin Reductase 1 ,030217 neurology & neurosurgery ,Research Paper ,medicine.drug - 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., Graphical abstract Image 1
- Published
- 2020