PUBLICATION
Subcellular Photocatalysis Enables Tumor-Targeted Inhibition of Thioredoxin Reductase I by Organogold(I) Complexes
- Authors
- Liu, M., Liu, H., Yang, Y., Xiong, X., Zou, T.
- ID
- ZDB-PUB-250425-5
- Date
- 2025
- Source
- Journal of the American Chemical Society : (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Catalysis
- Photochemical Processes
- Animals
- Gold*/chemistry
- Gold*/pharmacology
- Mice
- Antineoplastic Agents*/chemical synthesis
- Antineoplastic Agents*/chemistry
- Antineoplastic Agents*/pharmacology
- Drug Screening Assays, Antitumor
- Coordination Complexes*/chemistry
- Coordination Complexes*/pharmacology
- Zebrafish
- Humans
- Thioredoxin Reductase 1*/antagonists & inhibitors
- Thioredoxin Reductase 1*/metabolism
- Cell Line, Tumor
- Prodrugs/chemistry
- Prodrugs/pharmacology
- Enzyme Inhibitors*/chemical synthesis
- Enzyme Inhibitors*/chemistry
- Enzyme Inhibitors*/pharmacology
- Light
- PubMed
- 40272019 Full text @ J. Am. Chem. Soc.
Citation
Liu, M., Liu, H., Yang, Y., Xiong, X., Zou, T. (2025) Subcellular Photocatalysis Enables Tumor-Targeted Inhibition of Thioredoxin Reductase I by Organogold(I) Complexes. Journal of the American Chemical Society. :.
Abstract
Selective inhibition of TrxR1 over TrxR2 is a highly sought-after goal, because the two enzymes play distinct roles in cancer progression. However, achieving targeted inhibition is challenging due to their high homology and identical active site sequence. Herein we report a new subcellular photocatalysis approach for targeted inhibition by controllably activating organogold(I) prodrugs within the cytosol, the exclusive location of TrxR1. The NHC-Au(I)-alkynyl complexes are stable and evenly distributed in the cell; they can meanwhile be efficiently transformed into active NHC-Au(I)-L species (L = labile ligands) via a radical mechanism by photocatalysts released into the cytosol (from endosome/lysosome) upon light irradiation, leading to selective inhibition of TrxR1 without affecting TrxR2. This results in strong cytotoxicity to cancer cells with much higher selectivity than auranofin, a pan TrxR inhibitor that cannot discriminate TrxR1/2, along with potent antitumor activities in multiple zebrafish and mouse models. This subcellular prodrug activation may thus suggest a novel approach to precision targeting using the remarkable spatial control of photocatalysis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping