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

ABSTRACT

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.

KEYWORDS:

• Thioredoxin reductase
• cancer
• redox homeostasis
• selenocysteine
• reactive oxygen species
• metal complexes
• Michael acceptors
• nitro (hetero)aromatic compounds

Article highlights

• TrxR is an important enzyme responsible for maintaining redox homeostasis in the cell.

• Perturbed TrxR functioning is linked primarily to cancer but also to other diseases such as neurodegeneration, inflammation, microbial infection, neonatal hyperoxic lung injury.

• TrxR inhibitors based on metal complexes, arsenic and selenium compounds have received less attention recently.

• New Michael acceptors, nitro (hetero)aromatic compounds as well as several miscellaneous chemotypes have emerged in the patent literature.

• Analysis of the non-patent literature suggests future trends in TrxR inhibitor design which include novel electrophilic compounds as well as various dual inhibitors.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This research was supported by Russian Foundation for Basic Research (project grant 19-33-60010).