Gold-templated covalent targeting of the CysSec-dyad of thioredoxin reductase 1 in cancer cells

Lukas Skos, Claudia Schmidt, Sophie R. Thomas, Mihyun Park, Verena Geiger, Dominik Wenisch, Riccardo Bonsignore, Giorgia Del Favero, Thomas Mohr, Andrea Bileck, Christopher Gerner, Angela Casini, Samuel M. Meier-Menches

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number102072
JournalCell Reports Physical Science
Volume5
Issue number7
DOIs
StatePublished - 17 Jul 2024

Keywords

  • arylation
  • cancer
  • chemoproteomics
  • covalent drug discovery
  • gold
  • thioredoxin reductase 1

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