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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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
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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.”
Background
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“Sofalcone (6) is a synthetic derivative of a sophoradin chalconoid, found in herbs of Sophora tonkinensis, which is used as traditional Chinese medicine.”
Background
Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain
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Background
Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway
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BackgroundInfluential
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BindingDB Entry 50023204: Discovery of β-amino acid substituted naphthalene sulfonamide derivatives as potent Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) protein-protein interaction inhibitors for ulcerative colitis management.
BindingDB (2026) · UC San Diego · doi:10.7270/q24t6q8p
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BindingDB (2021) · UC San Diego · doi:10.7270/q2qn6bbk
BindingDB Entry 50016446: Recent applications of vinyl sulfone motif in drug design and discovery.
BindingDB (2023) · UC San Diego · doi:10.7270/q20g3q5h
BindingDB Entry 50046392: Structure-Activity and Structure-Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1-Nrf2 Protein-Protein Interaction Inhibitor.
BindingDB (2016) · UC San Diego · doi:10.7270/q2cr5w5h
BindingDB Entry 50011439: Design, Synthesis, and Structure-Activity Relationships of Indoline-Based Kelch-like ECH-Associated Protein 1-Nuclear Factor (Erythroid-Derived 2)-Like 2 (Keap1-Nrf2) Protein-Protein Interaction Inhibitors.
BindingDB (2022) · UC San Diego · doi:10.7270/q2vd7329
BindingDB Entry 50017940: TBA
BindingDB (2023) · UC San Diego · doi:10.7270/q2q52trd
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BindingDB (2016) · UC San Diego · doi:10.7270/q2fn181b
BindingDB Entry 50020149: Optimization of the C2 substituents on the 1,4-bis(arylsulfonamido)naphthalene-N,N'-diacetic acid scaffold for better inhibition of Keap1-Nrf2 protein-protein interaction.
BindingDB (2024) · UC San Diego · doi:10.7270/q2cf9vjf
BindingDB Entry 50001714: Non-covalent Small-Molecule Kelch-like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1-Nrf2) Inhibitors and Their Potential for Targeting Central Nervous System Diseases.
BindingDB (2020) · UC San Diego · doi:10.7270/q2cj8h17
BindingDB Entry 50044153: Oxidative stress in Alzheimer's disease: are we connecting the dots?
BindingDB (2015) · UC San Diego · doi:10.7270/q2pk0hpv
BindingDB Entry 50023009: Covalent Inhibitors of KEAP1 with Exquisite Selectivity.
BindingDB (2026) · UC San Diego · doi:10.7270/q21z498d
BindingDB Entry 50006254: Non-electrophilic modulators of the canonical Keap1/Nrf2 pathway.
BindingDB (2020) · UC San Diego · doi:10.7270/q20v8gsc
BindingDB Entry 50012263: Discovery of 2-oxy-2-phenylacetic acid substituted naphthalene sulfonamide derivatives as potent KEAP1-NRF2 protein-protein interaction inhibitors for inflammatory conditions.
BindingDB (2022) · UC San Diego · doi:10.7270/q2fj2mgn
BindingDB Entry 50001541: Discovery of a head-to-tail cyclic peptide as the Keap1-Nrf2 protein-protein interaction inhibitor with high cell potency.
BindingDB (2020) · UC San Diego · doi:10.7270/q2pk0jnt
BindingDB Entry 50010105: Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Inhibition: An Emerging Strategy in Cancer Therapy.
BindingDB (2021) · UC San Diego · doi:10.7270/q2639t70
BindingDB Entry 50001797: Replacement of a Naphthalene Scaffold in Kelch-like ECH-Associated Protein 1 (KEAP1)/Nuclear Factor (Erythroid-derived 2)-like 2 (NRF2) Inhibitors.
BindingDB (2020) · UC San Diego · doi:10.7270/q2g163cr
BindingDB Entry 50016274: Structure-activity relationships of 1,4-bis(arylsulfonamido)-benzene or naphthalene-N,N'-diacetic acids with varying C2-substituents as inhibitors of Keap1-Nrf2 protein-protein interaction.
BindingDB (2023) · UC San Diego · doi:10.7270/q2f193rh
BindingDB Entry 50010098: Polar Recognition Group Study of Keap1-Nrf2 Protein-Protein Interaction Inhibitors.
BindingDB (2021) · UC San Diego · doi:10.7270/q2zk5m5r
BindingDB Entry 50048290: Activation of anti-oxidant Nrf2 signaling by substituted trans stilbenes.
BindingDB (2018) · UC San Diego · doi:10.7270/q23t9kdn
BindingDB Entry 50018063: Development of Noncovalent Small-Molecule Keap1-Nrf2 Inhibitors by Fragment-Based Drug Discovery.
BindingDB (2023) · UC San Diego · doi:10.7270/q2nv9pcr
BindingDB Entry 50042770: Target- and mechanism-based therapeutics for neurodegenerative diseases: strength in numbers.
BindingDB (2013) · UC San Diego · doi:10.7270/q23t9jkg
BindingDB Entry 50009297: Reasonably activating Nrf2: A long-term, effective and controllable strategy for neurodegenerative diseases.
BindingDB (2021) · UC San Diego · doi:10.7270/q2057kcz
BindingDB Entry 50018333: Recent progress in Keap1-Nrf2 protein-protein interaction inhibitors.
BindingDB (2024) · UC San Diego · doi:10.7270/q2b85dbt
BindingDB Entry 50014416: Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds.
BindingDB (2022) · UC San Diego · doi:10.7270/q24j0jx3
BindingDB Entry 50006692: Antioxidant, Anti-inflammatory, and Neuroprotective Effects of Novel Vinyl Sulfonate Compounds as Nrf2 Activator.
BindingDB (2021) · UC San Diego · doi:10.7270/q22b928h
BindingDB Entry 50046773: Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators.
BindingDB (2016) · UC San Diego · doi:10.7270/q25b04br
BindingDB Entry 50005346: Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction.
BindingDB (2020) · UC San Diego · doi:10.7270/q2v98c02
BindingDB Entry 50011110: Discovery of disubstituted xylylene derivatives as small molecule direct inhibitors of Keap1-Nrf2 protein-protein interaction.
BindingDB (2021) · UC San Diego · doi:10.7270/q22z193b
BindingDB Entry 50021431: Structural modification of C2-substituents on 1,4-bis(arylsulfonamido)benzene or naphthalene-N,N'-diacetic acid derivatives as potent inhibitors of the Keap1-Nrf2 protein-protein interaction.
BindingDB (2025) · UC San Diego · doi:10.7270/q2542t7c
BindingDB Entry 50021293: Cyclic Peptide Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Design, Synthesis, and In Vivo Treatment of Acute Lung Injury.
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BindingDB Entry 50016651: Design and synthesis of Osthole-based compounds as potential Nrf2 agonists.
BindingDB (2023) · UC San Diego · doi:10.7270/q2rb78nc
BindingDB Entry 50047995: Discovery and Development of Kelch-like ECH-Associated Protein 1. Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction Inhibitors: Achievements, Challenges, and Future Directions.
BindingDB (2018) · UC San Diego · doi:10.7270/q2377bpq
BindingDB Entry 50017688: Target Fishing Reveals a Novel Mechanism of 1,2,4-Oxadiazole Derivatives Targeting Rpn6, a Subunit of 26S Proteasome.
BindingDB (2023) · UC San Diego · doi:10.7270/q2bg2t24
BindingDB Entry 50012368: Development and optimization of halogenated vinyl sulfones as Nrf2 activators for the treatment of Parkinson's disease.
BindingDB (2022) · UC San Diego · doi:10.7270/q2222zf3
BindingDB Entry 50013670: Optimization of 1,4-bis(arylsulfonamido)naphthalene-N,N'-diacetic acids as inhibitors of Keap1-Nrf2 protein-protein interaction to suppress neuroinflammation.
BindingDB (2022) · UC San Diego · doi:10.7270/q2sj1qdq
BindingDB Entry 50010400: Synthesis and Evaluation of Noncovalent Naphthalene-Based KEAP1-NRF2 Inhibitors.
BindingDB (2021) · UC San Diego · doi:10.7270/q2q243sw
BindingDB Entry 50006108: Rapid identification of Keap1-Nrf2 small-molecule inhibitors through structure-based virtual screening and hit-based substructure search.
BindingDB (2020) · UC San Diego · doi:10.7270/q261139g
BindingDB Entry 50044159: Discovery of potent Keap1-Nrf2 protein-protein interaction inhibitor based on molecular binding determinants analysis.
BindingDB (2015) · UC San Diego · doi:10.7270/q2x3500x
Desoxo-narchinol A and water extract of Nardostachys jatamansi ameliorate house dust mite-induced atopic dermatitis by regulating Nrf2/HO-1 signaling
Shim, K., Kim, H. J., Baek, S.-J., Gu, D. R., Kim, Y. J., Kim, S., 채성욱, Kim, T., & Kim, K. M. (2026) · Fitoterapia · doi:10.1016/j.fitote.2026.107536

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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