Subcellular Photocatalysis Enables Tumor-Targeted Inhibition of Thioredoxin Reductase I by Organogold(I) Complexes

Area of Science:

• Biochemistry
• Chemical Biology
• Cancer Research

Background:

• Thioredoxin reductase 1 (TrxR1) and TrxR2 play distinct roles in cancer progression.
• Selective inhibition of TrxR1 over TrxR2 is a significant therapeutic goal.
• Achieving selectivity is challenging due to high homology and identical active site sequences between TrxR1 and TrxR2.

Purpose of the Study:

• To develop a novel subcellular photocatalysis approach for targeted inhibition of TrxR1.
• To achieve selective activation of organogold(I) prodrugs within the cytosol, the exclusive location of TrxR1.
• To demonstrate potent antitumor activities and high selectivity compared to existing inhibitors.

Main Methods:

• Utilizing NHC-Au(I)-alkynyl complexes as prodrugs that are stable and distributed within cells.
• Employing photocatalysts released from endosomes/lysosomes to activate prodrugs via a radical mechanism upon light irradiation.
• Investigating the subcellular activation mechanism and its effect on TrxR1 and TrxR2 inhibition.

Main Results:

• Controllable activation of organogold(I) prodrugs in the cytosol, leading to selective TrxR1 inhibition.
• Demonstrated significantly higher cytotoxicity to cancer cells compared to the pan TrxR inhibitor auranofin.
• Showcased potent antitumor activities in zebrafish and mouse models.

Conclusions:

• Subcellular photocatalysis offers a novel strategy for precision targeting by spatially controlling prodrug activation.
• This approach enables selective TrxR1 inhibition, providing a promising avenue for cancer therapy.
• The method overcomes the challenge of TrxR1/TrxR2 homology for targeted drug development.