Thioredoxin reductase inhibitors: a patent review

ABSTRACT

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.

KEYWORDS:

• Thioredoxin reductase
• cancer
• redox regulation
• selenocysteine
• metal complex
• Michael acceptor
• disulfide

Article highlights

• The TrxR enzymes play a pivotal role in regulating cellular redox signaling pathways.

• The malfunction of TrxR enzymes has been linked to many disorders, including cancer and neurodegeneration.

• TrxR inhibitors have been the subject of many patents, and are promising anticancer agents.

• Although numerous molecules have been discovered to inhibit TrxR enzymes with high potency, finding highly selective inhibitor of the enzymes is challenging.

• Novel strategies that might lead to selective target of TrxR enzymes were proposed.

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.

Additional information

Funding

J Fang has received financial support from the Natural Science Foundation of China (21572093) and the Natural Science Foundation of Gansu Province (145RJZA225).