Thioredoxin reductase inhibitors: a patent review

Introduction: Mammalian thioredoxin reductases (TrxRs) are selenocysteine-containing homodimeric flavin enzymes that catalyze the NADPH-dependent reduction of oxidized thioredoxins. Increasing evidence indicates that TrxRs are potential targets for anticancer drug development. This review summarizes patented inhibitors of mammalian TrxRs with an emphasis on those having potential applications in treatment of cancer. Areas covered: A background introduction of TrxR as well as the relevance of TrxR and cancer is provided in the first part of this review. Then, a brief discussion of TrxR assays is followed in the second part. The patented TrxRs' inhibitors that were categorized into four classes, i. e., metal complexes, Michael acceptors, sulfur/selenium-containing compounds and others, are summarized in the third part of the review. Expert opinion: There is currently no clinical anticancer drug that specifically targets TrxR. One major hurdle in finding a successful TrxR inhibitor as a therapeutic drug is the specific inhibition of TrxR by an inhibitor. As most inhibitors described in literature and patents target the selenol group in the C-terminus of TrxR enzymes, it is hard to avoid cross interactions of such inhibitors with thiols. Novel strategies are proposed to achieve discovery of highly selective inhibitors of TrxR enzymes.