Thioredoxin reductase inhibitors: updated patent review (2017-present)

Introduction: Thioredoxin reductase (TrxR) is a selenocysteine-containing enzyme which is responsible - as a part of the thioredoxin system - for maintaining redox homeostasis in cells. It is upregulated in cancerous state as a defense against oxidative stress. TrxR has been mostly considered an anticancer drug target although it has applications in other therapeutic areas such as neurodegeneration, inflammation, microbial infections, and neonatal hyperoxic lung injury. Areas covered: The present review covers the patent literature that appeared in the period 2017-2020, i.e. since the publication of the previous expert opinion patent review on TrxR inhibitors. The recent additions to the following traditional classes of inhibitors are discussed: metal complexes, Michael acceptors as well as arsenic and selenium compounds. At the same time, a novel group of nitro (hetero)aromatic compounds have emerged which likely acts via covalent inhibition mechanism. Several miscellaneous chemotypes are grouped under Miscellaneous subsection. Expert opinion: While specificity over glutathione reductase is achieved easily, TrxR is still moving toward the later stages of development at a very slow rate. Michael acceptors, particularly based on TRXR substrate-mimicking scaffolds, are gaining impetus and so are dual and hybrid compounds. The development prospects of the emerging nitro (hetero)aromatic chemotypes remain uncertain.