Gold-templated covalent targeting of the CysSec-dyad of thioredoxin reductase 1 in cancer cells
- Author(s)
- 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
- 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.
- Organisation(s)
- Department of Analytical Chemistry, Department of Inorganic Chemistry, Department of Food Chemistry and Toxicology, Core Facility Multimodal Imaging, Joint Metabolome Facility
- External organisation(s)
- Vienna Doctoral School in Chemistry (DoSChem), Technische Universität München, Università degli Studi di Palermo
- Journal
- Cell Reports Physical Science
- Volume
- 5
- DOI
- https://doi.org/10.1016/j.xcrp.2024.102072
- Publication date
- 07-2024
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 106052 Cell biology, 301904 Cancer research
- Keywords
- ASJC Scopus subject areas
- General Chemistry, General Materials Science, General Engineering, General Energy, General Physics and Astronomy
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/c18dfb9c-e580-4679-b5aa-3bd557e1c0cb