Research Topic

Small Molecule Inhibitors Targeting Mammalian Selenoprotein Thioredoxin Reductase (TXNRD): Interactions, Mechanisms and Applications

About this Research Topic

Selenoproteins have diverse functions involved in human development, health, and diseases. Mammalian thioredoxin reductase (TXNRD) enzymes are selenoproteins and key redox regulators in cells. The most outstanding function of TXNRD is to keep the thioredoxin (TXN) proteins in a reduced state, which further interact with multiple downstream proteins and regulate their functions. TXNRD is usually overexpressed in tumor tissues, and this overexpression is essential to keep tumor phenotypes, making targeting TXNRD inhibition an appealing strategy in cancer chemotherapy. Generally, TXNRD inhibition leads to redox imbalance in cells and causes accumulation of reactive oxygen species (ROS), which further triggers tumor cells death via different pathways. Increasing inhibitors of cytosolic TXNRD1 and mitochondrial TXNRD2 have been disclosed and some of them are under further development for cancer therapy in the past decades.

Currently, most TXNRD inhibitors are electrophiles and work via targeting the highly reactive selenocysteine (Sec) residue of the enzyme. This mode of interaction renders these inhibitors to hardly avoid binding to the thiol group of the more abundant Cysteine (Cys) residue, leading to unspecific inhibition of TXNRD in bench research and unwanted side effects in clinical trials. Thus, finding structurally-diverse inhibitors with novel targeting mechanism is urgently needed. Alternatively, the combination of TXNRD inhibitors with other molecules to low side effects and/or enhance efficacy may be another promising solution. Despite the importance of TXNRD inhibitors to medicine being increasingly recognized, only limited pharmaceutical companies are actively involved in the further development of TXNRD inhibitors. To expedite the application of TXNRD inhibitors in treating cancer or other diseases, it requires a close collaboration of academia and industry to facilitate translating the bench results to bedside trials.

This Research Topic expects to report the recent progresses on small molecules targeting TXNRD, to explore the interacting mechanisms of TXNRD inhibitors, and to reveal the connection between TXNRD inhibition and downstream signaling pathways. Also, studies on the application of TXNRD inhibitors in human diseases and clinical trials are highly welcome. Topics to be covered include, but not limited to, the following:

• Rationally designed molecules and natural molecules targeting mammalian TXNRD
• Novel approaches targeting mammalian TXNRD
• Pharmacology and toxicology of TXNRD inhibitors
• Evaluation of TXNRD-targeting nanodrugs or nanocarriers
• Regulation of signaling pathways by TXNRD inhibitors
• Clinical development of TXNRD inhibitors in cancer therapy
• Clinical potential of TXNRD inhibitors in treating other human diseases


Keywords: thioredoxin reductase, small molecule, selenoprotein, inhibitor, redox regulation, reactive oxygen species, cancer therapy


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

Selenoproteins have diverse functions involved in human development, health, and diseases. Mammalian thioredoxin reductase (TXNRD) enzymes are selenoproteins and key redox regulators in cells. The most outstanding function of TXNRD is to keep the thioredoxin (TXN) proteins in a reduced state, which further interact with multiple downstream proteins and regulate their functions. TXNRD is usually overexpressed in tumor tissues, and this overexpression is essential to keep tumor phenotypes, making targeting TXNRD inhibition an appealing strategy in cancer chemotherapy. Generally, TXNRD inhibition leads to redox imbalance in cells and causes accumulation of reactive oxygen species (ROS), which further triggers tumor cells death via different pathways. Increasing inhibitors of cytosolic TXNRD1 and mitochondrial TXNRD2 have been disclosed and some of them are under further development for cancer therapy in the past decades.

Currently, most TXNRD inhibitors are electrophiles and work via targeting the highly reactive selenocysteine (Sec) residue of the enzyme. This mode of interaction renders these inhibitors to hardly avoid binding to the thiol group of the more abundant Cysteine (Cys) residue, leading to unspecific inhibition of TXNRD in bench research and unwanted side effects in clinical trials. Thus, finding structurally-diverse inhibitors with novel targeting mechanism is urgently needed. Alternatively, the combination of TXNRD inhibitors with other molecules to low side effects and/or enhance efficacy may be another promising solution. Despite the importance of TXNRD inhibitors to medicine being increasingly recognized, only limited pharmaceutical companies are actively involved in the further development of TXNRD inhibitors. To expedite the application of TXNRD inhibitors in treating cancer or other diseases, it requires a close collaboration of academia and industry to facilitate translating the bench results to bedside trials.

This Research Topic expects to report the recent progresses on small molecules targeting TXNRD, to explore the interacting mechanisms of TXNRD inhibitors, and to reveal the connection between TXNRD inhibition and downstream signaling pathways. Also, studies on the application of TXNRD inhibitors in human diseases and clinical trials are highly welcome. Topics to be covered include, but not limited to, the following:

• Rationally designed molecules and natural molecules targeting mammalian TXNRD
• Novel approaches targeting mammalian TXNRD
• Pharmacology and toxicology of TXNRD inhibitors
• Evaluation of TXNRD-targeting nanodrugs or nanocarriers
• Regulation of signaling pathways by TXNRD inhibitors
• Clinical development of TXNRD inhibitors in cancer therapy
• Clinical potential of TXNRD inhibitors in treating other human diseases


Keywords: thioredoxin reductase, small molecule, selenoprotein, inhibitor, redox regulation, reactive oxygen species, cancer therapy


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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Submission Deadlines

11 July 2021 Manuscript

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Manuscripts can be submitted to this Research Topic via the following journals:

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Topic Editors

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Submission Deadlines

11 July 2021 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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