TY - JOUR

T1 - Thioredoxin reductase inhibitors

T2 - updated patent review (2017-present)

AU - Chupakhin, Evgeny

AU - Krasavin, Mikhail

N1 - Publisher Copyright: © 2021 Informa UK Limited, trading as Taylor & Francis Group.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - cancer

KW - metal complexes

KW - Michael acceptors

KW - nitro (hetero)aromatic compounds

KW - reactive oxygen species

KW - redox homeostasis

KW - selenocysteine

KW - Thioredoxin reductase

KW - Humans

KW - Neoplasms/drug therapy

KW - Thioredoxin-Disulfide Reductase/antagonists & inhibitors

KW - Thioredoxins/metabolism

KW - Enzyme Inhibitors/pharmacology

KW - Patents as Topic

KW - Oxidative Stress/drug effects

KW - Antineoplastic Agents/pharmacology

KW - Animals

KW - Drug Development

UR - http://www.scopus.com/inward/record.url?scp=85103157897&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/6210ec6b-0137-3460-a9bb-c6847d10185d/

U2 - 10.1080/13543776.2021.1899160

DO - 10.1080/13543776.2021.1899160

M3 - Review article

C2 - 33666133

AN - SCOPUS:85103157897

VL - 31

SP - 745

EP - 758

JO - Expert Opinion on Therapeutic Patents

JF - Expert Opinion on Therapeutic Patents

SN - 1354-3776

IS - 8

ER -