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 language | English |
|---|---|
| Article number | 102072 |
| Journal | Cell Reports Physical Science |
| Volume | 5 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 17 Jul 2024 |
Funding
The authors are grateful to the Core Facility for Mass Spectrometry, the Core Facility Multimodal Imaging (Faculty of Chemistry, University of Vienna), and the Joint Metabolome Facility (University of Vienna and Medical University of Vienna), which are all members of the Vienna Life-Science Instruments. S.M.M.-M. acknowledges financial support from the Austrian Science Fund (P33238-N). S.R.T. acknowledges the TUM Global Postdoc Fellowship Scheme for funding. The authors thank Endre Kiss for helpful assistance during the confocal microscopy experiments. Conceptualization, A.C. and S.M.M.-M. Methodology, L.S. C.S. C.G. A.C. and S.M.M.-M. Formal analysis, T.M. A.B. and C.G. Investigation, L.S. C.S. S.R.T. M.P. V.G. D.W. R.B. and G.D.F. Resources, G.D.F. C.G. A.C. and S.M.M.-M. Data curation, L.S. T.M. A.B. C.G. and S.M.M.-M. Writing \u2013 original draft, L.S. C.S. A.C. and S.M.M.-M. Writing \u2013 review and editing, all authors. Supervision, C.G. A.C. and S.M.M.-M. The authors declare no competing interests. The authors are grateful to the Core Facility for Mass Spectrometry, the Core Facility Multimodal Imaging (Faculty of Chemistry, University of Vienna), and the Joint Metabolome Facility (University of Vienna and Medical University of Vienna), which are all members of the Vienna Life-Science Instruments. S.M.M.-M. acknowledges financial support from the Austrian Science Fund ( P33238-N ). S.R.T. acknowledges the TUM Global Postdoc Fellowship Scheme for funding. The authors thank Endre Kiss for helpful assistance during the confocal microscopy experiments.
UN SDGs
This output contributes to the following UN Sustainable Development Goals (SDGs)
-
SDG 3 Good Health and Well-being
Austrian Fields of Science 2012
- 106052 Cell biology
- 301904 Cancer research
Keywords
- arylation
- cancer
- chemoproteomics
- covalent drug discovery
- gold
- thioredoxin reductase 1
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