A small molecule NRF2 activator BC-1901S ameliorates inflammation through DCAF1/NRF2 axis

Chen, Yanwen; Evankovich, John; Tuncer, Ferhan; Kennerdell, Jason R.; Camarco, Daniel P.; Shishido, Morgan S.; Liu, Yuan; Chen, Bill B.

doi:10.1016/j.redox.2020.101485

Cited by 17 publications

(13 citation statements)

References 36 publications

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“…Further, BC1618 directly interacted with Fbxo48 but not Fbxo30 (negative control) when measured by a Cellular Thermal Shift Assay (CETSA) ( Fig. 3C ) [ 19 – 21 ]. Dose-dependent BC1618-mediated increases in pAmpkα levels were not observed in siRNA -mediated Fbxo48 knockdown cells and in the knockdown cells, pAmpkα protein remained basally elevated but unchanged with increasing amounts of BC1618 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance

et al. 2021

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The AMP-activated protein kinase (Ampk) is a central regulator of metabolic pathways and increasing Ampk activity has been considered to be an attractive therapeutic target. Here, we identified an orphan ubiquitin E3 ligase subunit protein, Fbxo48, that targets the active, phosphorylated Ampkα (pAmpkα) for polyubiquitylation and proteasomal degradation. We generated a novel Fbxo48 inhibitory compound, BC1618, whose potency in stimulating Ampk-dependent signaling greatly exceeds AICAR or metformin. This compound increases the biological activity of Ampk not by stimulating the activation of Ampk, but rather by preventing activated pAmpkα from Fbxo48-mediated degradation. We demonstrate that consistent with augmenting Ampk activity, BC1618 promotes mitochondrial fission, facilitates autophagy, and improves hepatic insulin sensitivity in high fat diet-induced obese mice. Hence, we provide a unique bioactive compound that inhibits pAmpkα disposal. Together, these results define a new pathway regulating Ampk biological activity and demonstrate the potential utility of modulating this pathway for therapeutic benefit.

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Section: Resultsmentioning

confidence: 99%

A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance

et al. 2021

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“…As such, we concentrated our mechanistic studies on the latter, likely more clinically viable agent, demonstrating that TMPRSS2 is targeted for proteasomal-mediated degradation. We have previously described an unbiased siRNA-mediated strategy to rapidly identify which of the more than 600 E3 ubiquitin ligases are relevant for a given target’s half-life ( 38 ). Using that platform, we were able to identify DCAF1 as an important regulator of TMPRSS2 stability.…”

Section: Discussionmentioning

confidence: 99%

A high throughput screen for TMPRSS2 expression identifies FDA-approved and clinically advanced compounds that can limit SARS-CoV-2 entry

Chen

Evankovich

Larsen

et al. 2020

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SARS-CoV-2 (2019-nCoV) is the pathogenic coronavirus responsible for the global pandemic of COVID-19 disease. The Spike (S) protein of SARS-CoV-2 attaches to host lung epithelial cells through the cell surface receptor ACE2, a process dependent on host proteases including TMPRSS2. Here, we identified small molecules that can reduce surface expression of TMPRSS2 using a 2,700 FDA-approved or current clinical trial compounds. Among these, homoharringtonine and halofuginone appear the most potent agents, reducing endogenous TMPRSS2 expression at sub-micromolar concentrations. These effects appear to be mediated by a drug-induced alteration in TMPRSS2 protein stability. We further demonstrate that halofuginone modulates TMPRSS2 levels through proteasomal-mediated degradation that involves the E3 ubiquitin ligase component DDB1- and CUL4-associated factor 1 (DCAF1). Finally, cells exposed to homoharringtonine and halofuginone, at concentrations of drug known to be achievable in human plasma, demonstrated marked resistance to SARS-CoV-2 pseudoviral infection. Given the safety and pharmacokinetic data already available for the compounds identified in our screen, these results should help expedite the rational design of human clinical trials designed to combat COVID-19 infection.

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“…DCAF1 is a novel E3 ligase required for Nrf2 protein degradation [ 23 ]. Since miR-3175 silenced DCAF1, we then tested its effect on Nrf2 signaling.…”

Section: Resultsmentioning

confidence: 99%

“…miRNAs can activate the Nrf2 signaling cascade via silencing their target genes [ 20 – 22 ], thereby protecting osteoblasts from DEX. A recent study using the RNAi screening method has discovered the ubiquitin E3 ligase DDB1 and CUL4 associated factor 1 (DCAF1) as a noncanonical regulator of Nrf2 stability and signaling [ 23 ]. There is a direct interaction between Nrf2 and DCAF1, the latter can promote Nrf2 ubiquitination and degradation [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…A recent study using the RNAi screening method has discovered the ubiquitin E3 ligase DDB1 and CUL4 associated factor 1 (DCAF1) as a noncanonical regulator of Nrf2 stability and signaling [ 23 ]. There is a direct interaction between Nrf2 and DCAF1, the latter can promote Nrf2 ubiquitination and degradation [ 23 ]. In the present study, we identified a novel DCAF1-targeting miRNA, microRNA-3175 (miR-3175).…”

Section: Introductionmentioning

confidence: 99%

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DCAF1-targeting microRNA-3175 activates Nrf2 signaling and inhibits dexamethasone-induced oxidative injury in human osteoblasts

et al. 2021

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Activation of nuclear-factor-E2-related factor 2 (Nrf2) signaling can protect human osteoblasts from dexamethasone-induced oxidative injury. DDB1 and CUL4 associated factor 1 (DCAF1) is a novel ubiquitin E3 ligase for Nrf2 protein degradation. We identified a novel DCAF1-targeting miRNA, miR-3175. RNA pull-down, Argonaute 2 RNA-immunoprecipitation, and RNA fluorescent in situ hybridization results confirmed a direct binding between miR-3175 and DCAF1 mRNA in primary human osteoblasts. DCAF1 3′-untranslated region luciferase activity and its expression were significantly decreased after miR-3175 overexpression but were augmented with miR-3175 inhibition in human osteoblasts and hFOB1.19 osteoblastic cells. miR-3175 overexpression activated Nrf2 signaling, causing Nrf2 protein stabilization, antioxidant response (ARE) activity increase, and transcription activation of Nrf2-dependent genes in human osteoblasts and hFOB1.19 cells. Furthermore, dexamethasone-induced oxidative injury and apoptosis were largely attenuated by miR-3175 overexpression in human osteoblasts and hFOB1.19 cells. Importantly, shRNA-induced silencing or CRISPR/Cas9-mediated Nrf2 knockout abolished miR-3175 overexpression-induced osteoblast cytoprotection against dexamethasone. Conversely, DFAC1 knockout, by the CRISPR/Cas9 method, activated the Nrf2 cascade and inhibited dexamethasone-induced cytotoxicity in hFOB1.19 cells. Importantly, miR-3175 expression was decreased in necrotic femoral head tissues of dexamethasone-taking patients, where DCAF1 mRNA was upregulated. Together, silencing DCAF1 by miR-3175 activated Nrf2 signaling to inhibit dexamethasone-induced oxidative injury and apoptosis in human osteoblasts.

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A small molecule NRF2 activator BC-1901S ameliorates inflammation through DCAF1/NRF2 axis

Cited by 17 publications

References 36 publications

A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance

A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance

A high throughput screen for TMPRSS2 expression identifies FDA-approved and clinically advanced compounds that can limit SARS-CoV-2 entry

DCAF1-targeting microRNA-3175 activates Nrf2 signaling and inhibits dexamethasone-induced oxidative injury in human osteoblasts

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