Thioredoxin Reductase 1 Inhibitor 1

Thioredoxin reductase 1 inhibitor 1 (TRi-1) is an irreversible inhibitor of thioredoxin reductase 1 (TrxR1; IC₅₀ = 0.012 µM).¹ It inhibits TrxR1-induced reduction of Trx1 in a cell-free assay (IC₅₀ = 4.3 µM). TRi-1 (10 µM) reduces the mitochondrial oxygen consumption rate in HCT116 colorectal cancer cells. It increases the intracellular levels of hydrogen peroxide in FaDu head and neck squamous cell carcinoma (HNSCC) cells in a time- and concentration-dependent manner. TRi-1 decreases the viability of FaDu cells (IC₅₀ = 0.72 µM). In vivo, TRi-1 (10 mg/kg twice per day) decreases tumor growth in a FaDu HNSCC mouse xenograft model. It induces intratumoral apoptosis in a FaDu HNSCC mouse xenograft model when administered at a dose of 5 mg/kg daily. TRi-7 also is toxic to S. mansoni adult worms (LD₅₀ = 10.07 µM).²

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1. Stafford, W.C., Peng, X., Olofsson, M.H., et al. Irreversible inhibition of cytosolic thioredoxin reductase 1 as a mechanistic basis for anticancer therapy. Sci. Transl. Med. 10(428), eaaf7444 (2018).

2. Lyu, H., Petukhov, P.A., Banta, P.R., et al. Characterization of lead compounds targeting the selenoprotein thioredoxin glutathione reductase for treatment of schistosomiasis. ACS Infect. Dis. 6(3), 393-405 (2020).