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

Abstract

Mammalian thioredoxin reductase (TrxR) enzymes are homodimeric flavin proteins sharing a unique yet essential selenocysteine residue at their C-terminus. TrxRs, together with their endogenous substrate thioredoxins, play a crucial role in regulating diverse cellular redox events. A wealth of evidence from both clinic observations and bench studies supports that overactivation/dysfunction of TrxRs has a close link to the onset and development of various diseases, such as cancer and neurodegeneration. Thus, an increasing interest has been attracted to find small molecule modulators of TrxRs during the past years. Herein, we briefly discussed the relevance of targeting TrxRs inhibition for cancer treatment, and presented the small molecule inhibitors of mammalian TrxRs published in the nonpatent literatures from 2011 to 2016. The mechanisms of inhibition by different classes of molecules were summarized, and some inhibitors with promising anticancer activity were further discussed. We expect this work would be a comprehensive reference in the medicinal chemistry, and have a broad audience across multiple disciplines.

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 …”

“…The thioredoxin system, including thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH, regulates cellular signal pathways and proliferation . TrxR is the only known physiological enzyme that can catalyze the reduction of oxidized Trx . Many studies have shown that TrxR is involved in multifarious physiological and pathological processes, including apoptosis, chronic inflammation and cancer .…”

Targeting Thioredoxin Reductase by Ibrutinib Promotes Apoptosis of SMMC-7721 Cells

“…High expression of TrxR can help scavenge ROS and resist cell death. And various recent studies in the literature have reported that irreversible inhibition of TrxR could induce cancer cell apoptosis (Stafford et al, 2018;Zhuge et al, 2018;Zhang et al, 2019). Our studies have provided preliminary evidence that IBT could target mammalian TrxR for cancer therapy, which will give us more viewpoints to understand the cancer therapy mechanism.…”

“…We found that IBT has an a,b-unsaturated ketone reactive group which has been demonstrated to be an acceptable recognition site of the mammalian TrxR inhibitor. The approved structure, also including naphthoquinone, a-methylene-g-lactone moiety, and a,b-g,d-unsaturated lactone moiety, can inhibit TrxR activity due to its electrophilic propensity toward the nucleophilic groups of TrxR (Cai et al, 2012;Zhang et al, 2019).…”