Bis-Michael Acceptors as Novel Probes to Study the Keap1/Nrf2/ARE Pathway

Deny, Ludovic J.; Traboulsi, Hussein; Cantin, André M.; Marsault, Éric; Richter, Martin; Bélanger, Guillaume

doi:10.1021/acs.jmedchem.6b01132

Cited by 13 publications

(12 citation statements)

References 45 publications

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“…Electrophilic features may account for potential toxicity issues associated with off-target interactions. 34 When studied in SH-SY5Y cells the non-(pro)electrophilic compound 13 was not toxic in the whole range of tested concentrations (cell viability > 90%, Figure 2). Noteworthy, the behavior at 5 μM (concentration of interest for biological activity) of (pro)electrophilic compounds 2−12 was not significantly dissimilar from that of 13.…”

Section: ■ Results and Discussionmentioning

confidence: 93%

“…Moreover, when analyzing the induction of NQO1, all the compounds but 13 increased NQO1 levels, with the same trend of activity detected for Nrf2 activation and translocation to the nucleus (Figure c). Noteworthy, differently from what recently observed for other multielectrophile compounds, the combined presence of the two (pro)electrophilic features, as in 1 , did not result in a synergistic efficacy (compare activity of 1 with that of 9 and 12 , which only carry the catechol group). This can be possibly ascribed to the conjugation, occurring in 1 , between the two features, that consequently may not behave as separate entities.…”

Section: Resultsmentioning

confidence: 98%

“…Electrophilic features may account for potential toxicity issues associated with off-target interactions . When studied in SH-SY5Y cells the non-(pro)electrophilic compound 13 was not toxic in the whole range of tested concentrations (cell viability > 90%, Figure ).…”

Section: Resultsmentioning

confidence: 99%

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Targeting the Nrf2/Amyloid-Beta Liaison in Alzheimer’s Disease: A Rational Approach

Simoni

Serafini

Caporaso

et al. 2017

ACS Chem. Neurosci.

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Amyloid is a prominent feature of Alzheimer's disease (AD). Yet, a linear linkage between amyloid-β peptide (Aβ) and the disease onset and progression has recently been questioned. In this context, the crucial partnership between Aβ and Nrf2 pathways is acquiring paramount importance, offering prospects for deciphering the Aβ-centered disease network. Here, we report on a new class of antiaggregating agents rationally designed to simultaneously activate transcription-based antioxidant responses, whose lead 1 showed interesting properties in a preliminary investigation. Relying on the requirements of Aβ recognition, we identified the catechol derivative 12. In SH-SY5Y neuroblastoma cells, 12 combined remarkable free radical scavenger properties to the ability to trigger the Nrf2 pathway and induce the Nrf2-dependent defensive gene NQO1 by means of electrophilic activation of the transcriptional response. Moreover, 12 prevented the formation of cytotoxic stable oligomeric intermediates, being significantly more effective, and per se less toxic, than prototype 1. More importantly, as different chemical features were exploited to regulate Nrf2 and Aβ activities, the two pathways could be tuned independently. These findings point to compound 12 and its derivatives as promising tools for investigating the therapeutic potential of the Nrf2/Aβ cellular network, laying foundation for generating new drug leads to confront AD.

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Section: ■ Results and Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 98%

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Targeting the Nrf2/Amyloid-Beta Liaison in Alzheimer’s Disease: A Rational Approach

Simoni

Serafini

Caporaso

et al. 2017

ACS Chem. Neurosci.

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“…Keap1 is considered to be a tumor suppressor due to its ability to inhibit tumor progression (28). However, in the past years, Keap1 studies have mainly focused on antioxidative stress through the Keap1/Nrf2/ARE signaling pathway (29)(30)(31). It was reported that high methylation of CpG islands in the Keap1 promoter significantly downregulated its expression in NSCLC tissues and cells (32).…”

Section: Discussionmentioning

confidence: 99%

Keap1 Inhibits Metastatic Properties of NSCLC Cells by Stabilizing Architectures of F-Actin and Focal Adhesions

Yang

Sun

et al. 2018

Molecular Cancer Research

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Low expression of the tumor suppressor Kelch-like ECH-associated protein 1 (KEAP1) in non-small cell lung cancer (NSCLC) often results in higher malignant biological behavior and poor prognosis; however, the underlying mechanism remains unclear. The present study demonstrates that overexpression of Keap1 significantly suppresses migration and invasion of three different lung cancer cells (A549, H460, and H1299). Highly expressed Keap1, compared with the control, promotes formation of multiple stress fibers with larger mature focal adhesion complexes in the cytoplasm where only fine focal adhesions were observed in the membrane under control conditions. RhoA activity significantly increased when Keap1 was overexpressed, whereas Myosin 9b expression was reduced but could be rescued by proteasome inhibition. Noticeably, mouse tumor xenografts with Keap1 overexpression were smaller in size and less metastatic relative to the control group. Taken together, these results demonstrate that Keap1 stabilizes F-actin cytoskeleton structures and inhibits focal adhesion turnover, thereby restraining the migration and invasion of NSCLC. Therefore, increasing Keap1 or targeting its downstream molecules might provide potential therapeutic benefits for the treatment of patients with NSCLC. This study provides mechanistic insight on the metastatic process in NSCLC and suggests that Keap1 and its downstream molecules may be valuable drug targets for NSCLC patients. .

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“…Recently, bis-Michael acceptors have been developed to regulate the Keap1/Nrf2/ARE pathway, which supports our approach. 43 Our design would also enable the rapid synthesis of analogues in comparison to helenalin, which required lengthy total syntheses. 44–47 Herein, we report the design, synthesis, and characterization of simplified helenalin analogues and their utilization in cell culture to target p65 of the canonical NF-κB signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Targeting NF-κB p65 with a Helenalin Inspired Bis-electrophile

et al. 2016

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The canonical NF-κB signaling pathway is a mediator of the cellular inflammatory response and a target for developing therapeutics for multiple human diseases. The furthest downstream proteins in the pathway, the p50/p65 transcription factor heterodimer, have been recalcitrant towards small molecule inhibition despite the substantial number of compounds known to inhibit upstream proteins in the activation pathway. Given the roles of many of these upstream proteins in multiple biochemical pathways, targeting the p50/p65 heterodimer offers an opportunity for enhanced on-target specificity. Towards this end, the p65 protein presents two non-disulfide cysteines, Cys38 and Cys120, at its DNA-binding interface that are amenable to targeting by covalent molecules. The natural product helenalin, a sesquiterpene lactone, has been previously shown to target Cys38 on p65 and ablate its DNA-binding ability. Using helenalin as inspiration, simplified helenalin analogues were designed, synthesized, and shown to inhibit induced canonical NF-κB signaling in cell culture. Moreover, two simplified helenalin probes were proficient at forming covalent protein adducts, binding to Cys38 on recombinant p65, and targeting p65 in HeLa cells without engaging canonical NF-κB signaling proteins IκBα, p50, and IKKα/β. These studies further support that targeting the p65 transcription factor-DNA interface with covalent small molecule inhibitors is a viable approach towards regulating canonical NF-κB signaling.

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Bis-Michael Acceptors as Novel Probes to Study the Keap1/Nrf2/ARE Pathway

Cited by 13 publications

References 45 publications

Targeting the Nrf2/Amyloid-Beta Liaison in Alzheimer’s Disease: A Rational Approach

Targeting the Nrf2/Amyloid-Beta Liaison in Alzheimer’s Disease: A Rational Approach

Keap1 Inhibits Metastatic Properties of NSCLC Cells by Stabilizing Architectures of F-Actin and Focal Adhesions

Targeting NF-κB p65 with a Helenalin Inspired Bis-electrophile

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