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

Autor: Christian M. Beusch, Hjalmar Gullberg, Katarina Johansson, Bo Lundgren, Amir Ata Saei, Pierre Sabatier, Per I. Arvidsson, Elias S.J. Arnér, Roman A. Zubarev
Jazyk: angličtina
Rok vydání: 2020
Předmět:
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
Zdroj: Redox Biology, Vol 32, Iss, Pp-(2020)
Redox Biology
ISSN: 2213-2317
Popis: 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
Databáze: OpenAIRE
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