TY - JOUR
T1 - Gold-templated covalent targeting of the CysSec-dyad of thioredoxin reductase 1 in cancer cells
AU - Skos, Lukas
AU - Schmidt, Claudia
AU - Thomas, Sophie R.
AU - Park, Mihyun
AU - Geiger, Verena
AU - Wenisch, Dominik
AU - Bonsignore, Riccardo
AU - Del Favero, Giorgia
AU - Mohr, Thomas
AU - Bileck, Andrea
AU - Gerner, Christopher
AU - Casini, Angela
AU - Meier-Menches, Samuel M.
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2024/7/17
Y1 - 2024/7/17
N2 - 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.
AB - 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.
KW - arylation
KW - cancer
KW - chemoproteomics
KW - covalent drug discovery
KW - gold
KW - thioredoxin reductase 1
UR - http://www.scopus.com/inward/record.url?scp=85198334137&partnerID=8YFLogxK
U2 - 10.1016/j.xcrp.2024.102072
DO - 10.1016/j.xcrp.2024.102072
M3 - Article
AN - SCOPUS:85198334137
SN - 2666-3864
VL - 5
JO - Cell Reports Physical Science
JF - Cell Reports Physical Science
IS - 7
M1 - 102072
ER -