Thioredoxin reductase inhibitors: a patent review

Abstract

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.

A Gold(I) Complex Containing an Oleanolic Acid Derivative as a Potential Anti‐Ovarian‐Cancer Agent by Inhibiting TrxR and Activating ROS‐Mediated ERS

“…As effective inhibition of TrxR by gold complex 4 b was demonstrated, the binding sites between TrxR and 4 b were analyzed by molecular docking software (Figure B). SEC498/CYS497 residues are widely considered as the crucial active sites of TrxR and involved in the interaction of the enzyme with complexes . In particular, amino acid SEC498 is always considered to be an inhibitor targeting site.…”

“…The template Glide fitness score was set to evaluate the affinity. The possible binding sites of 4 b were analyzed and validated according to the literature …”

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

“…The two subunits of dimeric mammalian TrxRs assemble in a head‐to‐tail pattern, and these enzymes also share a similar catalysis mechanism (Figure ) . For the detailed structures and catalysis mechanisms of TrxRs, readers are recommended to refer to the recent publications . Reduced Trxs perform most functions of the thioredoxin system via interacting with various downstream proteins to form oxidized Trxs, and the disulfide bridge in the active site of oxidized Trxs must be regenerated to a dithiol form by TrxRs.…”

“…Due to the integral role that TrxRs play in regulating apoptosis and their elevated expression in many malignant cells, it is increasingly recognized that TrxRs are critically involved in the different stages of tumor development . Thus, there is an expanding interest in developing small molecules to interfere with the functions of thioredoxin system, especially the TrxR enzymes, for cancer treatment …”

“…In the animal experiments, knockout of either TrxR1 or TrxR2 causes embryonic death of mice . The physiological/pathological significance of the thioredoxin system inhibition and the structural character of TrxR enzymes have been detailed by several review articles . Readers are referred to these references for more information.…”