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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.
Liu et al. (Thu,) studied this question.