Heteroaromatic 4-arylquinols are novel inducers of Nuclear factor-erythroid 2-related factor 2 (Nrf2)

Wong, Daphne Pei Wen; Wells, Geoff; Hagen, Thilo

doi:10.1016/j.ejphar.2010.06.040

Cited by 7 publications

(8 citation statements)

References 19 publications

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“…Recently, synthetic compounds, such as heteroaromatic 4‐arylquinol (PMX‐290, 38 ), a compound with known antiproliferative activity in vitro and antitumor activity in vivo in tumor xenografts, and AI‐1 ( 39 ), a quinolinone derivative identified in a cell‐based high‐throughput screening assay of chemical libraries, were shown to induce Nrf2. Structurally, they all contain Michael acceptors that can react with sulfhydryl groups.…”

Section: Modulators Of Keap1‐nrf2‐are Pathwaymentioning

confidence: 99%

Small Molecule Modulators of Keap1‐Nrf2‐ARE Pathway as Potential Preventive and Therapeutic Agents

Magesh

Chen

2012

Medicinal Research Reviews

677

577

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Keap1-Nrf2-ARE pathway represents one of the most important cellular defense mechanisms against oxidative stress and xenobiotic damage. Activation of Nrf2 signaling induces the transcriptional regulation of ARE-dependent expression of various detoxifying and antioxidant defense enzymes and proteins. Keap1-Nrf2-ARE signaling has become an attractive target for the prevention and treatment of oxidative stress-related diseases and conditions including cancer, neurodegenerative, cardiovascular, metabolic and inflammatory diseases. Over the last few decades, numerous Nrf2 inducers have been developed and some of them are currently undergoing clinical trials. Recently, over-activation of Nrf2 has been implicated in cancer progression as well as in drug resistance to cancer chemotherapy. Thus, Nrf2 inhibitors could potentially be used to improve the effectiveness of cancer therapy. Herein, we review the signaling mechanism of Keap1-Nrf2-ARE pathway, its disease relevance, and currently known classes of small molecule modulators. We also discuss several aspects of Keap1-Nrf2 interaction, Nrf2-based peptide inhibitor design, and the screening assays currently used for the discovery of direct inhibitors of Keap1-Nrf2 interaction.

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Section: Modulators Of Keap1‐nrf2‐are Pathwaymentioning

confidence: 99%

Small Molecule Modulators of Keap1‐Nrf2‐ARE Pathway as Potential Preventive and Therapeutic Agents

Magesh

Chen

2012

Medicinal Research Reviews

677

577

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“…This indicates that the mechanism of arsenite is Cys151 independent, as previously reported [ 21 ]. We also used two other NRF2 inducing compounds, PMX290 [ 19 ] and sulforaphane. PMX290 induced NRF2 protein levels in a Cys151 independent manner ( Fig 2C ), whereas the effect of sulforaphane was Cys151 dependent, consistent with previous reports [ 12 – 16 , 19 , 21 , 22 ].…”

Section: Resultsmentioning

confidence: 99%

“…The plasmid constructs, including NRF2-HA-pcDNA3, wild type and mutant FLAG-KEAP1-pcDNA3.1 and V5-KEAP1-pcDNA3.1, CUL3-V5-pcDNA3, CUL3-HA-pcDNA3 [ 18 , 19 ]. The Antioxidant Response Element (ARE)-luciferase-pGL2 reporter plasmid was a kind gift from Dr. Alan Porter [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

Regulation of the NRF2 transcription factor by andrographolide and organic extracts from plant endophytes

Wong

Leung

et al. 2018

PLoS ONE

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The transcription factor NF-E2 Related Factor-2 (NRF2) is an important drug target. Activation of NRF2 has chemopreventive effects in cancer and exerts beneficial effects in a number of diseases, including neurodegenerative diseases, inflammatory diseases, hepatosteatosis, obesity and insulin resistance. Hence, there have been great efforts to discover and characterize novel NRF2 activators. One reported NRF2 activator is the labdane diterpenoid andrographolide. In this study, we identified the mechanism through which andrographolide activates NRF2. We showed that andrographolide inhibits the function of KEAP1, a protein that together with CUL3 and RBX1 forms an E3 ubiquitin ligase that polyubiquitinates NRF2. Andrographolide partially inhibits the interaction of KEAP1 with CUL3 in a manner dependent on Cys151 in KEAP1. This suggests that andrographolide forms Michael acceptor dependent adducts with Cys151 in KEAP1 in vivo, leading to inhibition of NRF2 ubiquitination and consequently accumulation of the transcription factor. Interestingly, we also showed that at higher concentrations andrographolide increases NRF2 protein expression in a Cys151 independent, but likely KEAP1 dependent manner, possibly through modification of other Cys residues in KEAP1. In this study we also screened secondary metabolites produced by endophytes isolated from non-flowering plants for NRF2-inducing properties. One of the extracts, ORX 41, increased both NRF2 protein expression and transcriptional activity markedly. These results suggest that endophytes isolated from non-flowering or other plants may be a good source of novel NRF2 inducing compounds.

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“…The IC 50 values of chlorophyllin sodium copper salt and bonaphton were 35.7 and 37.9 μM, respectively. To confirm that these compounds disrupt the interaction between Keap1 and Nrf2 by an alternative experiment other than FCS, we further performed co-immunoprecipitation assay that was used for the verification of disruption of Keap1 protein-protein interaction by the other drugs 28 . Thus, we immunoprecipitated Keap1 from cells and tested whether addition of the drugs could dissociate coimmunoprecipitated Nrf2, and found that the compounds induced consistent decrease in binding between the two proteins.…”

Section: Resultsmentioning

confidence: 99%

Drug-Repositioning Screening for Keap1-Nrf2 Binding Inhibitors using Fluorescence Correlation Spectroscopy

Yoshizaki

Mori

Ishigami‐Yuasa

et al. 2017

Sci Rep

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The Kelch-like ECH-associating protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) signaling pathway is the major regulator of cytoprotective responses to oxidative and electrophilic stress. The Cul3/Keap1 E3 ubiquitin ligase complex interacts with Nrf2, leading to Nrf2 ubiquitination and degradation. In this study, we focused on the disruption of the Keap1-Nrf2 interaction to upregulate Nrf2 expression and the transcription of ARE-controlled cytoprotective oxidative stress response enzymes, such as HO-1. We completed a drug-repositioning screening for inhibitors of Keap1-Nrf2 protein-protein interactions using a newly established fluorescence correlation spectroscopy (FCS) screening system. The binding reaction between Nrf2 and Keap1 was successfully detected with a KD of 2.6 μM using our FCS system. The initial screening of 1,633 drugs resulted in 12 candidate drugs. Among them, 2 drugs significantly increased Nrf2 protein levels in HepG2 cells. These two promising drugs also upregulated ARE gene promoter activity and increased HO-1 mRNA expression, which confirms their ability to dissociate Nrf2 and Keap1. Thus, drug-repositioning screening for Keap1-Nrf2 binding inhibitors using FCS enabled us to find two promising known drugs that can induce the activation of the Nrf2-ARE pathway.

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Heteroaromatic 4-arylquinols are novel inducers of Nuclear factor-erythroid 2-related factor 2 (Nrf2)

Cited by 7 publications

References 19 publications

Small Molecule Modulators of Keap1‐Nrf2‐ARE Pathway as Potential Preventive and Therapeutic Agents

Small Molecule Modulators of Keap1‐Nrf2‐ARE Pathway as Potential Preventive and Therapeutic Agents

Regulation of the NRF2 transcription factor by andrographolide and organic extracts from plant endophytes

Drug-Repositioning Screening for Keap1-Nrf2 Binding Inhibitors using Fluorescence Correlation Spectroscopy

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