The DOI matches its Crossref record; 275 of the 275 references it cites were found in a registry or an index.
Small Molecule Modulators of Keap1‐ Nrf2‐ ARE Pathway as Potential Preventive and Therapeutic Agents
Open accessAbstract
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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“Mitochondria are responsible for the production of the majority of ROS within a cell, and these potentially harmful radicals are modulated by the expression of endogenous antioxidants involving the nuclear factor erythroid 2-related factor 2 (Nrf2)- kelch-like ECH-associated protein 1 (Keap1) pathway [Magesh et al., 2012] or via external anti-oxidants in the diet [Birch-Machin and Oyewole 2015;”
From Oxidative stress and ageing (2016) · cites this paper as Magesh et al., 2012
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2 retracted
Nuclear Import and Export Signals in Control of Nrf2
Jain, A. K., Bloom, D. A., & Jaiswal, A. K. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m502083200 · Cited by 195
RetractedPing, Z., Liu, W., Kang, Z., Cai, J., Wang, Q., Cheng, N., Wang, S., Wang, S., Zhang, J. H., & Sun, X. (2010) · Brain Research · doi:10.1016/j.brainres.2010.04.036 · Cited by 153
RetractedOxidants, oxidative stress and the biology of ageing
Finkel, T., & Holbrook, N. J. (2000) · Nature · doi:10.1038/35041687 · Cited by 9,413
Metals, Toxicity and Oxidative Stress
Valko, M., Morris, H., & Cronin, M. (2005) · Current Medicinal Chemistry · doi:10.2174/0929867053764635 · Cited by 5,018
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“Sesquiterpenes such as zumberone (18)180 and isoalantolactone (19),181 and terpenoids containing α,β-unsaturated fragrant aldehydes182 such as perillaldehyde (20) and citral (21) were shown to induce Nrf2-mediated expression of detoxifying enzymes.”
BackgroundNeurodegenerative diseases and oxidative stress
Barnham, K. J., Masters, C. L., & Bush, A. I. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1330 · Cited by 3,683 · cited 2×
“Sofalcone (6) is a synthetic derivative of a sophoradin chalconoid, found in herbs of Sophora tonkinensis, which is used as traditional Chinese medicine.”
BackgroundItoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D., & Yamamoto, M. (1999) · Genes & Development · doi:10.1101/gad.13.1.76 · Cited by 3,634 · cited 1×
“Sesquiterpenes such as zumberone (18)180 and isoalantolactone (19),181 and terpenoids containing α,β-unsaturated fragrant aldehydes182 such as perillaldehyde (20) and citral (21) were shown to induce Nrf2-mediated expression of detoxifying enzymes.”
BackgroundCell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway
Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.46.120604.141046 · Cited by 3,630 · cited 2×
“Investigation of ARE-inducing activities of monocyclic systems such as MCE-1 (27) and MCE5 (28) demonstrated that 27 was approximately twofold less potent than 26, but approximately tenfold more potent than 28.”
BackgroundInfluentialThe chemical diversity and distribution of glucosinolates and isothiocyanates among plants
Fahey, J. W., Zalcmann, A. T., & Talalay, P. (2001) · Phytochemistry · doi:10.1016/s0031-9422(00)00316-2 · Cited by 2,968
BIOLOGY AND BIOCHEMISTRY OF GLUCOSINOLATES
Halkier, B. A., & Gershenzon, J. (2006) · Annual Review of Plant Biology · doi:10.1146/annurev.arplant.57.032905.105228 · Cited by 2,279
Research works printed but not linked: 2
- 10.1038/sj.emboj.7601243 · DOI · Paper page
- 10.1016/j.chembiol.2011.03.013 · DOI
Cited by
Sorted by citations
Chalcone: A Privileged Structure in Medicinal Chemistry
Zhuang, C., Zhang, W., Sheng, C., Zhang, W., Xing, C., & Miao, Z. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00020 · Cited by 1,538
The emerging role of the Nrf2–Keap1 signaling pathway in cancerPreprint
Jaramillo, M. C., & Zhang, D. D. (2013) · Genes & Development · doi:10.1101/gad.225680.113 · Cited by 1,326
“Several other small molecules have been found to suppress the Nrf2 pathway, including ascorbic acid, luteolin, ochratoxin A, trigonelline, and all-trans retinoic acid (ATRA) (for review, see Magesh et al. 2012).”
BackgroundGlutathione metabolism in cancer progression and treatment resistance
Bansal, A., & Simon, M. C. (2018) · The Journal of Cell Biology · doi:10.1083/jcb.201804161 · Cited by 1,253
“Therefore, more thorough research needs to be performed to discover effective and highly selective inhibitors of NRF2 activity (Magesh et al., 2012).”
BackgroundLu, H., Zhou, Q., He, J., Jiang, Z., Peng, C., Tong, R., & Shi, J. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00315-3 · Cited by 891
“As a result, the long term application of the Keap1/Nrf2 inhibitors results in the accumulation of the active Nrf2, which may trigger other problems like cancer(178) Therefore, finding non-covalent small molecules that directly interfere with the Keap–Nrf2 interaction, dissociating the two and exerting antioxidant def…”
BackgroundThe Keap1–Nrf2–ARE Pathway As a Potential Preventive and Therapeutic Target: An Update
Lu, M., Ji, J., Jiang, Z., & You, Q. (2016) · Medicinal Research Reviews · doi:10.1002/med.21396 · Cited by 815
Metadata
- Authors
- Magesh, S., Chen, Y., & Hu, L.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Hu, Longqin
- ORCID
- Venue
- Medicinal Research Reviews
- Publisher
- Wiley
- Published
- 2012-05
- Volume
- 32
- Issue
- 4
- Pages
- 687-726
- ISSN
- 0198-6325 (ISSN-L)
- 1098-1128
- 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
- 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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