Discovery of Potent, Novel Nrf2 Inducers Via Quantum Modeling, Virtual Screening, and <i>In Vitro</i> Experimental Validation

Williamson, Tracy P.; Amirahmadi, Sara; Joshi, Gururaj; Kaludov, Nikola; Martinov, Martin; Johnson, Dale G.; Johnson, Jeffrey A.

doi:10.1111/cbdd.12040

Cited by 17 publications

(12 citation statements)

References 36 publications

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“…Numerous cell‐based and in silico screens have identified Nrf2‐activating compounds (Schaap, Hancock, Wilderspin, & Wells, 2013; Wang et al, 2013; Williamson et al, 2012; Wu, McDonald, Liu, Chaguturu, & Klaassen, 2012), including triterpenoid 2‐cyano‐3,12‐dioxooleana‐1,9(11)‐dien‐28‐oate‐methylamide (CDDO‐MA), puerarin, sulforaphane, CDDO‐ethyl amide and others. Nrf2 activators demonstrated activity in in vitro and in vivo in different neurodegenerative mouse models, protecting neurons, decreasing the accumulation of aberrant proteins and increasing life span (Buendia et al, 2016; Joshi and Johnson 2012).…”

Section: Potential Therapeutic Targets In Astrocytesmentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

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Section: Potential Therapeutic Targets In Astrocytesmentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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“…In recent years, research has been highly focused toward the discovery of new Nrf2-related drugs, including high-throughput screening approaches,127–132 structure-based modeling,133 and the testing and development of molecules that target the Nrf2 pathway 80,134–140…”

Section: Drugs Targeting Nrf2mentioning

confidence: 99%

The clinical potential of influencing Nrf2 signaling in degenerative and immunological disorders

Gao¹,

Doan²,

Hybertson³

2014

CPAA

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Nuclear factor (erythroid-derived 2)-like 2 (Nrf2; encoded in humans by the NFE2L2 gene) is a transcription factor that regulates the gene expression of a wide variety of cytoprotective phase II detoxification and antioxidant enzymes through a promoter sequence known as the antioxidant-responsive element (ARE). The ARE is a promoter element found in many cytoprotective genes; therefore, Nrf2 plays a pivotal role in the ARE-driven cellular defense system against environmental stresses. Agents that target the ARE/Nrf2 pathway have been tested in a wide variety of disorders, with at least one new Nrf2-activating drug now approved by the US Food and Drug Administration. Examination of in vitro and in vivo experimental results, and taking into account recent human clinical trial results, has led to an opinion that Nrf2-activating strategies – which can include drugs, foods, dietary supplements, and exercise – are likely best targeted at disease prevention, disease recurrence prevention, or slowing of disease progression in early stage illnesses; they may also be useful as an interventional strategy. However, this rubric may be viewed even more conservatively in the pathophysiology of cancer. The activation of the Nrf2 pathway has been widely accepted as offering chemoprevention benefit, but it may be unhelpful or even harmful in the setting of established cancers. For example, Nrf2 activation might interfere with chemotherapies or radiotherapies or otherwise give tumor cells additional growth and survival advantages, unless they already possess mutations that fully activate their Nrf2 pathway constitutively. With all this in mind, the ARE/Nrf2 pathway remains of great interest as a possible target for the pharmacological control of degenerative and immunological diseases, both by activation and by inhibition, and its regulation remains a promising biological target for the development of new therapies.

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“…1–4 Targeting the Keap1-Nrf2-ARE signaling pathway represents an attractive strategy to discover chemopreventive agents for cancer as well as preventive and therapeutic agents for a variety of other diseases and conditions, including diabetes, Alzheimer’s, and Parkinson’s, that involve oxidative stress and inflammation. 5–13 …”

mentioning

confidence: 99%

Discovery of a small-molecule inhibitor and cellular probe of Keap1–Nrf2 protein–protein interaction

Hu¹,

Magesh²,

Chen³

et al. 2013

Bioorganic & Medicinal Chemistry Letters

171

178

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A high-throughput screen (HTS) of the MLPCN library using a homogenous fluorescence polarization assay identified a small molecule as a first-in-class direct inhibitor of Keap1-Nrf2 protein-protein interaction. The HTS hit has three chiral centers; a combination of flash and chiral chromatographic separation demonstrated that Keap1-binding activity resides predominantly in one stereoisomer (SRS)-5 designated as ML334 (LH601A), which is at least 100× more potent than the other stereoisomers. The stereochemistry of the four cis isomers was assigned using X-ray crystallography and confirmed using stereospecific synthesis. (SRS)-5 is functionally active in both an ARE gene reporter assay and an Nrf2 nuclear translocation assay. The stereospecific nature of binding between (SRS)-5 and Keap1 as well as the preliminary but tractable structure-activity relationships support its use as a lead for our ongoing optimization.

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Discovery of Potent, Novel Nrf2 Inducers Via Quantum Modeling, Virtual Screening, and In Vitro Experimental Validation

Cited by 17 publications

References 36 publications

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

The clinical potential of influencing Nrf2 signaling in degenerative and immunological disorders

Discovery of a small-molecule inhibitor and cellular probe of Keap1–Nrf2 protein–protein interaction

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