Non-electrophilic modulators of the canonical Keap1/Nrf2 pathway

Richardson, Benjamin G; Jain, Atul D.; Speltz, Thomas E.; Moore, Terry W.

doi:10.1016/j.bmcl.2015.04.019

Cited by 69 publications

(54 citation statements)

References 70 publications

(107 reference statements)

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“…To overcome the pitfall of selectivity, a new class of NRF2 inducers that prevent the docking of NRF2 to KEAP1 has emerged (Richardson et al, 2015). The use of PPI inhibitors has been achieved by the prior elucidation of the X-ray crystal structure of KEAP1 (Padmanabhan et al, 2006) bound to a peptide containing the high-affinity binding ETGE motif of NRF2 (Lo et al, 2006).…”

Section: B Protein-protein Interaction Inhibitors For Nuclear Factormentioning

confidence: 99%

“…Systems Medicine Approach to NRF2 in Chronic Diseases Five families of PPI inhibitors have been described: tetrahydroisoquinoline (Jnoff et al, 2014;Richardson et al, 2015), thiopyrimidine (Marcotte et al, 2013), naphthalene (Jiang et al, 2014b), carbazone (Ranjan et al, 2014), and urea derivatives (Sato et al, 2013). Table 3 compiles recent patents addressing these small molecules.…”

Section: B Protein-protein Interaction Inhibitors For Nuclear Factormentioning

confidence: 99%

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Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

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Section: B Protein-protein Interaction Inhibitors For Nuclear Factormentioning

confidence: 99%

Section: B Protein-protein Interaction Inhibitors For Nuclear Factormentioning

confidence: 99%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

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“…All the Nrf2 activators presented above exemplify electrophilic activators of Nrf2, but there is also an increasing interest in developing non-electrophilic molecules that can activate this pathway (see Richardson et al, 2015, for a review).…”

Section: Nrf2 Activatorsmentioning

confidence: 99%

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Esteras¹,

Dinkova‐Kostova²,

Abramov³

2016

Biological Chemistry

143

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Abstract:The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor wellknown for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich's ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.

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“…Owing to the competitive and reversible nature, the Keap1-Nrf2 PPI inhibitors may show some advantages toward the electrophilic Nrf2 activators. 14 Recently, a series of Keap1-Nrf2 PPI inhibitors, including peptides 15−17 and small molecules, 18−23 have been identified. Among these agents, the diacetate compound series showed the most predominant PPI inhibition activity.…”

mentioning

confidence: 99%

Polar Recognition Group Study of Keap1-Nrf2 Protein–Protein Interaction Inhibitors

Tan

et al. 2016

ACS Med. Chem. Lett.

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Directly disrupting the Keap1-Nrf2 protein−protein interaction (PPI) has emerged as an attractive way to activate Nrf2, and Keap1-Nrf2 PPI inhibitors have been proposed as potential agents to relieve inflammatory and oxidative stress diseases. In this work, we investigated the diacetic moiety around the potent Keap1-Nrf2 PPI inhibitor DDO1018 (2), which was reported by our group previously. Exploration of bioisosteric replacements afforded the ditetrazole analog 7, which maintains the potent PPI inhibition activity (IC 50 = 15.8 nM) in an in vitro fluorescence polarization assay. Physicochemical property determination demonstrated that ditetrazole replacement can improve the drug-like property, including elevation of pK a , log D, and transcellular permeability. Additionally, 7 is more efficacious than 2 on inducing the expression of Nrf2-dependent gene products in cells. This study provides an alternative way to replace the diacetic moiety and occupy the polar subpockets in Keap1, which can benefit the subsequent development of Keap1-Nrf2 PPI inhibitor.

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Non-electrophilic modulators of the canonical Keap1/Nrf2 pathway

Cited by 69 publications

References 70 publications

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Polar Recognition Group Study of Keap1-Nrf2 Protein–Protein Interaction Inhibitors

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