Probe Development Summary for Modulators of Mammalian Selenoprotein Thioredoxin Reductase 1 (TrxR1)
The following assay summarizes ongoing efforts in the development of chemical probes that are either inhibitors or substrates of mammalian selenoprotein thioredoxin reductase 1 (TrxR1). ..more
The following assay summarizes ongoing efforts in the development of chemical probes that are either inhibitors or substrates of mammalian selenoprotein thioredoxin reductase 1 (TrxR1).
The selenoprotein thioredoxin reductase (TrxR; EC 18.104.22.168) is a FAD containing homodimeric pyridine nucleotide-disulfide oxidoreductase with many cellular roles. Together with NADPH and its prime substrate thioredoxin (Trx), the enzyme forms the core of the Trx system. The mammalian Trx system exerts a wide spectrum of functions including redox regulation, antioxidant defense, regulation of transcription factors as well as support of cell growth and replication. Many of these functions involve the reduction of Trx, which may subsequently reduce a number of different substrates including ribonucleotide reductase, peroxiredoxins or NFkB. Mammalian TrxR itself also has a broad substrate specificity, reducing both protein and non-protein substrates, including low molecular weight compounds such as dehydroascorbate, lipoic acid, ubiquinone, and juglone. In addition, several drugs in clinical use for anticancer treatment are indeed known to target TrxR1.
Cellular processes involving selenium and selenoproteins are thought to have a major impact on the development and therapy of cancer. Of special interest in this setting is the targeting of TrxR1. Several recent studies argue for TrxR1 being an important anticancer drug target. The enzyme is frequently upregulated in a variety of tumors presumably leading to an advantage in cell replication and antioxidant defense. The importance of TrxR1 for in vivo tumor progression in mice xenograft models was furthermore demonstrated by Yoo et al., showing that knockdown of TrxR1 prevented tumor formation. It was also shown that TrxR1 knockdown inhibits self-sufficient growth and DNA replication of cancer cells. Moreover, it has been demonstrated that the levels of TrxR1 in tumor cells can influence the outcome of cytotoxic drug treatment in a drug dependent manner, e.g. with cisplatin showing increased cytotoxicity at high TrxR1 levels while other redox cycling drugs are less cytotoxic under such conditions.
This assay will be updated during the course of the probe development process.
Assay Provider: Elias Arner, Karolinska Institute
Screening Center PI: Austin, C.P.
Screening Center: NIH Chemical Genomics Center [NCGC]
Please see related BioAssays for all protocols relevant to this probe development project.
Comments will be added as small molecule probes are developed during the course of this work.