Cited by 795Genomics, phytochemicals, and oxidative stressRedox biology and oxidative stressBioactive Compounds and Antitumor Agents

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

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Magesh, Sadagopan, Chen, Yu, Hu, Longqin·2012·Medicinal Research Reviews

DOI 10.1002/med.21257PMC PMC3393814

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Abstract

Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response elements (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, overactivation 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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Background
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Background
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Authors: Magesh, S., Chen, Y., & Hu, L.
Affiliations: Rutgers, The State University of New Jersey (US)
Corresponding author: Hu, Longqin
ORCID: Chen, Yu
Hu, Longqin
Venue: Medicinal Research Reviews
Publisher: Wiley
Published: 2012-05
Volume: 32
Issue: 4
Pages: 687-726
ISSN: 0198-6325 (ISSN-L)
1098-1128
DOI: 10.1002/med.21257
PMC: PMC3393814
OpenAlex: W1767659454
Cited by: 760
References: 275
Citations by year: 2026: 30 · 2025: 39 · 2024: 52 · 2023: 61 · 2022: 69 · 2021: 58 · 2020: 85 · 2019: 81 · 2018: 54 · 2017: 63 · 2016: 41 · 2015: 56 · 2014: 42 · 2013: 28 · 2012: 1
FWCI: 3.79
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Medicinal Research Reviews (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (CA133791, CA125868, MH093197)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
Keywords: Nrf2/Keap1 pathway, Nrf2, Keap1, antioxidant response element, small molecule modulators, Nrf2 inducers, Nrf2 inhibitors, oxidative stress, xenobiotic detoxification, antioxidant defense, cancer chemotherapy resistance, peptide inhibitors, Keap1-Nrf2 interaction
MeSH terms: Animals, Anti-Inflammatory Agents, Antineoplastic Agents, Antioxidants, Humans, Hypoglycemic Agents, Signal Transduction, Oxidative Stress, Neuroprotective Agents, Response Elements, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2

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

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