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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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“Oltipraz (Magesh et al., 2012) ameliorated lamin B1 and HP1g levels by 73% and 53% (100% = difference between WT and HGPS cells), respectively (p < 0.05; Figure S5C), and showed some effect in reducing LAP2 and H3K27me3 defects (30%–38%, p > 0.05).”
InfluentialMitochondria‐targeted antioxidants
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“ARE system by Nrf2 agonist; this might protect the brain injury caused by the ROS (Magesh et al. 2012).”
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“Interest in modulating the antioxidant response pathway has led to the development of a number of NRF2-activating compounds, some of which are already in clinical use (Davies et al., 2016; Gao et al., 2014; Magesh et al., 2012).”
BackgroundOncogenic KRAS Confers Chemoresistance by Upregulating NRF2
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“Furthermore, all-trans-retinoic acid (ATRA) is able to suppress the Nrf2 pathway [184].”
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“Cumulative experimental evidence [153,154], and more recent evidence provided by several clinical trials [155,156], indicate that molecules that are able to induce the activation of Nrf2 could become an effective means to prevent and/or treat a number of pathological and/or toxicological conditions whose common etiolo…”
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Suliman, H. B., & Piantadosi, C. A. (2015) · Pharmacological Reviews · doi:10.1124/pr.115.011502 · Cited by 267
“Inactivation of Keap1 permits Nrf2 to enter the nucleus and bind to promoter AREs (Cheng et al., 2011;Dinkova-Kostova andAbramov, 2015), responsible for antioxidant gene expression as well as the expression of the p62 mitophagy protein (Dinkova-Kostova and Abramov, 2015).”
BackgroundInfluentialStructure of the BTB Domain of Keap1 and Its Interaction with the Triterpenoid Antagonist CDDO
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TrxR1 as a Potent Regulator of the Nrf2-Keap1 Response System
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“The same classes of compounds that inhibit TrxR1 (39) have been shown to also activate the Keap1-Nrf2 pathway (204), which may not be surprising as the mechanism for Keap1 inactivation involves modification of thiol groups, while TrxR1 is inhibited by similar targeting of its highly TARGETING OF TRXR1 AS ACTIVATOR MEC…”
BackgroundReactive oxygen species-mediated therapeutic response and resistance in glioblastoma
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“have classified around 90 natural or synthetic Nrf2 chemical activators as follows: (1) Michael acceptors; (2) oxidizable phenols and quinones; (3) isothiocyanates and sulfoxythiocarbamates; (4) dithiolethiones and diallyl sulfides; (5) trivalent arsenicals; (6) vicinal dimercaptans; (7) selenium-based compounds; (8)…”
BackgroundResveratrol, an Nrf2 activator, ameliorates aging-related progressive renal injury
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BackgroundVitamin D cell signalling in health and disease
Berridge, M. J. (2015) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2015.01.008 · Cited by 215
Discovery of a small-molecule inhibitor and cellular probe of Keap1–Nrf2 protein–protein interaction
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BackgroundPhytochemicals as Anti-Inflammatory Agents in Animal Models of Prevalent Inflammatory Diseases
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BackgroundGlutathione: Role in Oxidative/Nitrosative Stress, Antioxidant Defense, and Treatments
Raj, S. R., Bhattacharyya, C., Sarkar, A., Chakraborty, S., Sircar, E., Dutta, S., & Sengupta, R. (2021) · ChemistrySelect · doi:10.1002/slct.202100773 · Cited by 155
Matzinger, M., Fischhuber, K., Pölöske, D., Mechtler, K., & Heiß, E. H. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101393 · Cited by 148
“Next we addressed signaling behavior of WT and mutant Nrf2 in transfected cells upon treatment with sulforaphane (Sfn), a small natural molecule known to activate both Nrf2-and AMPK signaling [26,27].”
BackgroundTargeting Nrf2 Signaling to Combat Chemoresistance
No, J. H., Kim, Y.-B., & Song, Y. S. (2014) · Journal of Cancer Prevention · doi:10.15430/jcp.2014.19.2.111 · Cited by 146
“Keap1 has 5 functional domains including Kelch, intervening region (IVR), broad complex/tramtrack, Bric-a-Brac domain (BTB), an N-terminal region (NTR), and a C-terminal region (CTR).(3) Cysteine”
Target- and Mechanism-Based Therapeutics for Neurodegenerative Diseases: Strength in Numbers
Trippier, P. C., Labby, K. J., Hawker, D. D., Mataka, J., & Silverman, R. B. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm3015926 · Cited by 141
Recent applications of vinyl sulfone motif in drug design and discovery
Ahmadi, R., & Emami, S. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114255 · Cited by 144
Controversy about pharmacological modulation of Nrf2 for cancer therapy
Milković, L., Žarković, N., & Saso, L. (2017) · Redox Biology · doi:10.1016/j.redox.2017.04.013 · Cited by 142
“sequences and the activation of the pathway is blocked [29,47].”
BackgroundTranscription factor NRF2 as a promising therapeutic target for Alzheimer’s disease
Qu, Z., Sun, J., Zhang, W., Yu, J., & Zhuang, C. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.06.028 · Cited by 145
Therapeutic Targeting of the NRF2 Signaling Pathway in Cancer
Telkoparan‐Akillilar, P., Panieri, E., Cevik, D., Süzen, S., & Saso, L. (2021) · Molecules · doi:10.3390/molecules26051417 · Cited by 148
“KEAP1 was identified as a negative regulator of NRF2 that consists of five functional domains, namely, the N-terminal domain, Broad complex/Tramtrack, Bric-a-Brac domain (BTB), a cysteine-rich intervening region (IVR), Kelch domain, or double glycine repeat (DGR), and carboxyterminal domain (Figure 1B) [27].”
BackgroundDelgado-Roche, L., Riera‐Romo, M., Mesta, F., Hernández-Matos, Y., Barrios, J. M., Martínez-Sánchez, G., & Al-Dalaien, S. M. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.06.017 · Cited by 169
Nrf2 activation through the inhibition of Keap1–Nrf2 protein–protein interaction
Lee, S., & Hu, L. (2020) · Medicinal Chemistry Research · doi:10.1007/s00044-020-02539-y · Cited by 140
Zhang, J., Li, M., Zhang, G., Tian, Y. T., Kong, F., Xiong, S., Zhao, S., Jia, D. T., Manyande, A., & Du, H. (2020) · Food Chemistry · doi:10.1016/j.foodchem.2020.127921 · Cited by 137
Hassan, S. S. U., Samanta, S., Dash, R., Karpiński, T. M. M., Habibi, E., Sadiq, A., Ahmadi, A., & BUNGAU, S. G. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1015835 · Cited by 139
“Fisetin prevents the degradation of Nrf2 and increases its concentration, which advances the transcription of ARE-controlled antioxidant genes (Lee et al., 2011; Magesh et al., 2012; Reddy et al., 2021).”
BackgroundPeng, S., Zhang, B., Meng, X., Yao, J., & Fang, J. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00410 · Cited by 136
Turpaev, K. T. (2013) · Biochemistry (Moscow) · doi:10.1134/s0006297913020016 · Cited by 135
Toth, R. K., & Warfel, N. A. (2017) · Antioxidants · doi:10.3390/antiox6020027 · Cited by 136
Catechins: Protective mechanism of antioxidant stress in atherosclerosis
Sheng, Y., Sun, Y., Tang, Y., Yu, Y., Wang, J., Zheng, F., Li, Y., & Sun, Y. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1144878 · Cited by 134
“It then interacts with ARE in target genes (Magesh et al., 2012), to drive the expression of antioxidant genes, such as NQO1, HO-1, SOD and GPx (Figuer 3) (Satoh et al.”
BackgroundModulation of NRF2 signaling pathway by nuclear receptors: Implications for cancer
Namani, A., Li, Y., Wang, X. J., & Tang, X. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.05.003 · Cited by 128
Jiang, Z., Lu, M., & You, Q. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00586 · Cited by 128
Bertrand, H. C., Schaap, M., Baird, L., Georgakopoulos, N., Fowkes, A., Thiollier, C., Kaatchi, H., Dinkova‐Kostova, A. T., & Wells, G. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00602 · Cited by 123
Edwards, M. R., Johnson, B., Mire, C. E., Xü, W., Shabman, R. S., Speller, L. N., Leung, D. W., Geisbert, T. W., Amarasinghe, G. K., & Basler, C. F. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.01.043 · Cited by 120
“…explanation as to how the mVP24-Keap1 interaction triggers Nrf2 nuclear localization. mVP24 Expression Activates ARE-Directed Gene Expression Stimuli that disrupt the Nrf2-Keap1 interaction and promote Nrf2 nuclear localization activate expression of ARE genes (reviewed in Magesh et al., 2012).”
Shen, Q., Ji, F., Guo, H., Su, X., Zhu, B., Yao, X., Wang, Y., Cao, A., Wang, H., & Wang, L. (2023) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2023.03.022 · Cited by 122
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“In fact, several well-established antioxidants, cytoprotective, and putative chemopreventive agents have been shown to act via inhibition of KEAP1 and consequential activation of Nrf2 (reviewed in (30)).”
BackgroundPharmacological Applications of Antioxidants: Lights and Shadows
Saso, L., & Firuzi, O. (2014) · Current Drug Targets · doi:10.2174/1389450115666141024113925 · Cited by 119
“It should be mentioned that Nrf2 activation can also have a downside in certain types of cancer; in some tumors, Nrf2 is persistently activated due to somatic mutations in either Nrf2 or Keap1 and thus promoting tumor growth and resistance to oxidants and antineoplastic drugs [76, 83, 88-91].”
BackgroundArora, R., Sawney, S., Saini, V., Steffi, C., Tiwari, M., & Saluja, D. (2016) · Molecular Cancer · doi:10.1186/s12943-016-0550-2 · Cited by 117
“It is a basic region-leucine zipper (bZIP) protein belonging to Cap ‘n’ Collar (CNC) family of transcription factors and binds to Antioxidant Response Element (ARE) present in promoter of a battery of genes coding for antioxidant proteins [17].”
Wang, S., Xu, Y., Weng, Y., Fan, X., Bai, Y., Zheng, X., Lou, L.-J., & Zhang, F. (2018) · Food and Chemical Toxicology · doi:10.1016/j.fct.2018.02.041 · Cited by 116
Chemopreventive activity of sulforaphane
Jiang, X. M., Liu, Y., Ma, L., Ji, R., Qu, Y., Xin, Y., & Lv, G. (2018) · Drug Design Development and Therapy · doi:10.2147/dddt.s100534 · Cited by 115
“43,44 SFN can react with the thiol groups of Keap1 to form thionoacyl adducts, which enables Nrf2 to escape Keap1-dependent ubiquitination and degradation, leading to nuclear localization of Nrf2.”
BackgroundKoeberle, S. C., Kipp, A. P., Stuppner, H., & Koeberle, A. (2023) · Medicinal Research Reviews · doi:10.1002/med.21933 · Cited by 117
Chian, S., Li, Y., Wang, X. J., & Tang, X. (2014) · Asian Pacific Journal of Cancer Prevention · doi:10.7314/apjcp.2014.15.6.2911 · Cited by 114
Dual protection of hydroxytyrosol, an olive oil polyphenol, against oxidative damage in PC12 cells
Peng, S., Zhang, B., Yao, J., Duan, D., & Fang, J. (2015) · Food & Function · doi:10.1039/c5fo00097a · Cited by 112
Counteracting role of nuclear factor erythroid 2-related factor 2 pathway in Alzheimer's disease
Sharma, V., Kaur, A., & Singh, T. G. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110373 · Cited by 116
Pallesen, J. S., Tran, K. T., & Bach, A. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00358 · Cited by 112
The clinical potential of influencing Nrf2 signaling in degenerative and immunological disorders
Hybertson, B. M., Gao, B., & Doan, A. (2014) · Clinical Pharmacology Advances and Applications · doi:10.2147/cpaa.s35078 · Cited by 113
Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators
Jain, A. D., Potteti, H. R., Richardson, B. G., Kingsley, L. J., Luciano, J. P., Ryuzoji, A. F., Lee, H., Krunić, A., Mesecar, A. D., Reddy, S. P., et al. (2015) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2015.08.049 · Cited by 111
“Recently, there has been great interest in developing reversible covalent drugs to activate Nrf2 [31,32]; however, we and others have taken a different approach and have begun to develop noncovalent compounds that might be more selective Nrf2 activators [31,33e37].”
BackgroundProtective Effects of Melatonin on the Skin: Future Perspectives
Rusanova, I., Martínez-Ruiz, L., Florido, J., Rodríguez-Santana, C., Guerra‐Librero, A., Acuña-Castroviejo, D., & Escames, G. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20194948 · Cited by 111
“Due to the exposure of cells to ROS, Nrf2 can be translocated to the nucleus and activate gene expression of a series of antioxidative and cytoprotective proteins including heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase, quinone 1 (NQO1), γ-glutamyl-cystein synthase (γ-GCS), glutathione peroxidase (GPx), glutathionine…”
BackgroundInfluentialKang, Y., Song, Y., Luo, Y., Song, J. T., Li, C., Yang, S., Guo, J., Yu, J. M., & Zhang, X. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.08.037 · Cited by 110
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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