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Skos, Lukas, Schmidt, Claudia, Thomas, Sophie R. 
ORCID: https://orcid.org/0000-0003-1110-430X, Park, Mihyun, Geiger, Verena, Wenisch, Dominik, Bonsignore, Riccardo, Favero, Giorgia Del, Mohr, Thomas, Bileck, Andrea, Gerner, Christopher, Casini, Angela and Meier-Menches, Samuel M.
(2024)
Gold-templated covalent targeting of the CysSec-dyad of thioredoxin reductase 1 in cancer cells.
Cell Reports Physical Science, 5 (7).
ISSN 2666-3864
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Abstract
Covalent drugs emerged as a promising addition to the arsenal of medicinal chemistry tools. Here, a gold-templated mechanism is exploited to enable the selective covalent targeting of the CysSec-dyad of thioredoxin reductase 1 (TXNRD1) in cancer cells. This two-step mechanism involves reversible coordination of a cyclometalated gold(III) compound, featuring a bidentate CˆN ligand, to thiolates/selenolates, followed by reductive elimination and irreversible covalent cross-coupling reaction of the ligand to these nucleophiles. Following this reactivity, potent inhibition of TXNRD1 activity was shown in vitro, including cancer cell extracts. Selective arylation of the CysSec-dyad in the presence of reducing equivalents was seen in cell-free studies. Chemoproteomic studies showed that the proposed mechanism is selective toward specific protein targets, including TXNRD1. Proteome profiling revealed down-regulation of the detected selenoproteins, except TXNRD1, and induction of the NRF2-KEAP1 pathway. Metal-templated covalent targeting may prove useful to rationally expand the ligandable space of covalent drug discovery.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | arylation,cancer,chemoproteomics,covalent drug discovery,gold,thioredoxin reductase 1,general chemistry,general materials science,general engineering,general energy,general physics and astronomy,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1600/1600 |
| Faculty \ School: | Faculty of Science > School of Chemistry, Pharmacy and Pharmacology |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 15 Sep 2026 14:58 |
| Last Modified: | 16 Sep 2026 11:14 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/104541 |
| DOI: | 10.1016/j.xcrp.2024.102072 |
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