Recent progress in the development of small molecule Nrf2 activators: a patent review (2017-present)

References

• Finkel THolbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000;408:239–247.
   PubMed Web of Science ®Google Scholar
• Barnham KJ, Masters CL, Bush AI. Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov. 2004;3:205–214.
   PubMed Web of Science ®Google Scholar
• Kensler TW, Wakabayash N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Ann Rev Pharmacol Toxicol. 2007;47:89–116.
   PubMed Web of Science ®Google Scholar
• Benz CC, Yau C. Ageing, oxidative stress and cancer: paradigms in parallax. Nat Rev Cancer. 2008;8:875–879.
   PubMed Web of Science ®Google Scholar
• Hu R, Saw CL, Yu R, et al. Regulation of NF-E2-Related Factor 2 signaling for cancer chemoprevention: antioxidant coupled with antiinflammatory. Antioxid Redox Sign. 2010;13:1679–1698.
   PubMed Web of Science ®Google Scholar
• Cho HY, Reddy SP, Kleeberger SR. Nrf2 defends the lung from oxidative stress. Antioxid Redox Sign. 2006;8:76–87.
   PubMed Web of Science ®Google Scholar
• Lyakhovich VV, Vavilin VA, Zenkov NK, et al. Active defense under oxidative stress. The antioxidant responsive element. Biochemistry-Moscow. 2006;71:962–974.
   PubMed Web of Science ®Google Scholar
• Itoh K, Wakabayashi N, Katoh Y, et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999;13:76–86.
   PubMed Web of Science ®Google Scholar
• Nioi P, Nguyen T, Sherratt PJ, et al. The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation. Mol Cell Biol. 2005;25:10895–10906.
   PubMed Web of Science ®Google Scholar
• Katoh Y, Itoh K, Yoshida E, et al. Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells. 2001;6:857–868.
   PubMed Web of Science ®Google Scholar
• Lu MC, Ji JA, Jiang ZY, et al. The Keap1-Nrf2-ARE pathway as a potential preventive and therapeutic target: an update. Med Res Rev. 2016;36:924–963.
   PubMed Web of Science ®Google Scholar
• Chowdhry S, Zhang Y, McMahon M, et al. Nrf2 is controlled by two distinct beta-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. Oncogene. 2013;32:3765–3781.
   PubMed Web of Science ®Google Scholar
• McMahon M, Thomas N, Itoh K, et al. Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redox-insensitive Neh6 degron. J Biol Chem. 2004;279:31556–31567.
   PubMed Web of Science ®Google Scholar
• Itoh K, Chiba T, Takahashi S, et al. An Nrf2 small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun. 1997;236:313–322.
   PubMed Web of Science ®Google Scholar
• Wang H, Liu K, Geng M, et al. RXRalpha inhibits the NRF2-ARE signaling pathway through a direct interaction with the Neh7 domain of NRF2. Cancer Res. 2013;73:3097–3108.
   PubMed Web of Science ®Google Scholar
• Namani A, Li Y, Wang XJ, et al. Modulation of NRF2 signaling pathway by nuclear receptors: implications for cancer. BBA-Mol Cell Res. 2014;1843:1875–1885.
   PubMed Web of Science ®Google Scholar
• Wakabayashi N, Itoh K, Wakabayashi J, et al. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet. 2003;35:238–245.
   PubMed Web of Science ®Google Scholar
• Yamamoto T, Suzuki T, Kobayashi A, et al. Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Mol Cell Biol. 2008;28:2758–2770.
   PubMed Web of Science ®Google Scholar
• Li W, Kong A-N. Molecular Mechanisms of Nrf2-Mediated Antioxidant Response. Mol Carcinog. 2009;48:91–104.
   PubMed Web of Science ®Google Scholar
• Itoh K, Mimura J, Yamamoto M. Discovery of the negative regulator of Nrf2, Keap1: a historical overview. Antioxid Redox Sign. 2010;13:1665–1678.
   PubMed Web of Science ®Google Scholar
• Lo S-C, Li X, Henzl MT, et al. Structure of the Keap1: Nrf2 interface provides mechanistic insight into Nrf2 signaling. Embo J. 2006;25:3605–3617.
   PubMed Web of Science ®Google Scholar
• Zhang DD, Lo SC, Cross JV, et al. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol. 2004;24:10941–10953.
   PubMed Web of Science ®Google Scholar
• Dinkova-Kostova AT, Holtzclaw WD, Cole RN, et al. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci USA. 2002;99:11908–11913.
   PubMed Web of Science ®Google Scholar
• Pallesen JS, Tran KT, Bach A. 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 CNS diseases. J Med Chem. 2018;61:8088–8103.
   PubMed Web of Science ®Google Scholar
• Jiang ZY, Lu MC, You QD. 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. J Med Chem. 2016;59:10837–10858.
   PubMed Web of Science ®Google Scholar
• Magesh S, Chen Y, Hu L. Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents. Med Res Rev. 2012;32:687–726.
   PubMed Web of Science ®Google Scholar
• Richardson BG, Jain AD, Speltz TE, et al. Non-electrophilic modulators of the canonical Keap1/Nrf2 pathway. Bioorg Med Chem Lett. 2015;25:2261–2268.
   PubMed Web of Science ®Google Scholar
• Tong KI, Padmanabhan B, Kobayashi A, et al. Different electrostatic Potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response. Mol Cell Biol. 2007;27:7511–7521.
   PubMed Web of Science ®Google Scholar
• Tong KI, Katoh Y, Kusunoki H, et al. Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol Cell Biol. 2006;26:2887–2900.
   PubMed Web of Science ®Google Scholar
• Baird L, Swift S, Lleres D, et al. Monitoring Keap1-Nrf2 interactions in single live cells. Biotechnol Adv. 2014;32:1133–1144.
   PubMed Web of Science ®Google Scholar
• Kensler TW, Wakabayashi N. Nrf2: friend or foe for chemoprevention? Carcinogenesis. 2010;31:90–99.
   PubMed Web of Science ®Google Scholar
• Copple IM. The Keap1-Nrf2 cell defense pathway–a promising therapeutic target? Adv Pharmacol (San Diego, CA). 2012;63:43–79.
   PubMedGoogle Scholar
• Hur W, Gray NS. Small molecule modulators of antioxidant response pathway. Curr Opin Chem Biol. 2011;15:162–173.
   PubMed Web of Science ®Google Scholar
• Wells G. Peptide and small molecule inhibitors of the Keap1-Nrf2 protein-protein interaction. Biochem Soc Trans. 2015;43:674–679.
   PubMed Web of Science ®Google Scholar
• Hong F, Freeman ML, Liebler DC. Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chem Res Toxicol. 2005;18:1917–1926.
   PubMed Web of Science ®Google Scholar
• Sporn MB, Liby KT. NRF2 and cancer: the good, the bad and the importance of context. Nat Rev Cancer. 2012;12:564–571.
   PubMed Web of Science ®Google Scholar
• Linker RA, Lee D-H, Ryan S, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011;134:678–692.
   PubMed Web of Science ®Google Scholar
• Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 Study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367:1098–1107.
   PubMed Web of Science ®Google Scholar
• Gold R. Placebo-controlled phase 3 Study of oral BG-12 for relapsing multiple sclerosis (vol 367, pg 1098, 2012). N Engl J Med. 2012;367:2362.
   Web of Science ®Google Scholar
• Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 Study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367:1087–1097.
   PubMed Web of Science ®Google Scholar
• Prosperini L, Pontecorvo S. Dimethyl fumarate in the management of multiple sclerosis: appropriate patient selection and special considerations. Ther Clin Risk Manag. 2016;12:339–350.
   PubMed Web of Science ®Google Scholar
• Jing X, Shi H, Zhang C, et al. Dimethyl fumarate attenuates 6-OHDA-induced neurotoxicity in SH-SY5Y cells and in animal model of Parkinson’s disease by enhancing Nrf2 activity. Neuroscience. 2015;286:131–140.
   PubMed Web of Science ®Google Scholar
• Lastres-Becker I, Garcia-Yague AJ, Scannevin RH, et al. Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson’s disease. Antioxid Redox Sign. 2016;25:61–77.
   PubMed Web of Science ®Google Scholar
• Wang Q, Chuikov S, Taitano S, et al. Dimethyl fumarate protects neural stem/progenitor cells and neurons from oxidative damage through Nrf2-ERK1/2 MAPK pathway. Int J Mol Sci. 2015;16:13885–13907.
   PubMed Web of Science ®Google Scholar
• Palte MJ, Wehr A, Tawa M, et al. Improving the gastrointestinal tolerability of fumaric acid esters: early findings on gastrointestinal events with diroximel fumarate in patients with relapsing-remitting multiple sclerosis from the phase 3, open-label EVOLVE-MS-1 study. Adv Ther. 2019;36:3154–3165.
   PubMed Web of Science ®Google Scholar
• Mrowietz U, Morrison PJ, Suhrkamp I, et al. The pharmacokinetics of fumaric acid esters reveal their in vivo effects. Trends Pharmacol Sci. 2018;39:1–12.
   PubMed Web of Science ®Google Scholar
• Zhang DD, Hannink M. Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol. 2003;23:8137–8151.
   PubMed Web of Science ®Google Scholar
• Axelsson AS, Tubbs E, Mecham B, et al. Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes. Sci Transl Med. 2017;9:eaah4477.
   PubMed Web of Science ®Google Scholar
• Bahadoran Z, Mirmiran P, Hosseinpanah F, et al. Broccoli sprouts powder could improve serum triglyceride and oxidized LDL/LDL-cholesterol ratio in type 2 diabetic patients: A randomized double-blind placebo-controlled clinical trial. Diabetes Res Clin Pract. 2012;96:348–354.
   PubMed Web of Science ®Google Scholar
• Holmstrom KM, Kostov RV, Dinkova-Kostova AT. The multifaceted role of Nrf2 in mitochondrial function. Curr Opin Pharmacol. 2016;1:80–91.
   Google Scholar
• Lee S, Choi B-R, Kim J, et al. Sulforaphane upregulates the heat shock protein co-chaperone CHIP and clears Amyloid-beta and Tau in a mouse model of Alzheimer’s disease. Mol Nutr Food Res. 2018;62:1800240.
   Web of Science ®Google Scholar
• Hou -T-T, Yang H-Y, Wang W, et al. Sulforaphane inhibits the generation of Amyloid-beta Oligomer and Promotes Spatial learning and memory in Alzheimer’s Disease (PS1V97L) transgenic mice. J Alzheimers Dis. 2018;62:1803–1813.
   PubMed Web of Science ®Google Scholar
• Sunkaria A, Bhardwaj S, Yadav A, et al. Sulforaphane attenuates postnatal proteasome inhibition and improves spatial learning in adult mice. J Nutr Biochem. 2018;51:69–79.
   PubMed Web of Science ®Google Scholar
• Klomparens EA, Ding Y. The neuroprotective mechanisms and effects of sulforaphane. Brain Circ. 2019;5:74–83.
   PubMedGoogle Scholar
• Alejandro B. Sulforaphane compositions and method for increasing bioavailability by ultrasonic techniques. MX20170014281. 2019.
   Google Scholar
• Frisbee A, Newsome P, Baudet M, et al. Stabilized sulforaphane. HUE039549T2. 2019.
   Google Scholar
• Honda T, Rounds BV, Bore L, et al. Synthetic oleanane and ursane triterpenoids with modified rings A and C: A series of highly active inhibitors of nitric oxide production in mouse macrophages. J Med Chem. 2000;43:4233–4246.
   PubMed Web of Science ®Google Scholar
• Sporn MB, Liby KT, Yore MM, et al. New synthetic triterpenoids: potent agents for prevention and treatment of tissue injury caused by inflammatory and oxidative stress. J Nat Prod. 2011;74:537–545.
   PubMed Web of Science ®Google Scholar
• Cleasby A, Yon J, Day PJ, et al. Structure of the BTB domain of Keap1 and its interaction with the Triterpenoid Antagonist CDDO. PLoS One. 2014;9:e98896.
   PubMed Web of Science ®Google Scholar
• Pergola PE, Raskin P, Toto RD, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med. 2011;365:327–336.
   PubMed Web of Science ®Google Scholar
• Zhang DD. Bardoxolone Brings Nrf2-Based Therapies to Light. Antioxid Redox Sign. 2013;19:517–518.
   PubMed Web of Science ®Google Scholar
• Sun H, Zhu J, Lin H, et al. Recent progress in the development of small molecule Nrf2 modulators: a patent review (2012-2016). Expert Opin Ther Pat. 2017;27:763–785.
   PubMed Web of Science ®Google Scholar
• Robledinos-Anton N, Fernandez-Gines R, Manda G, et al. Activators and inhibitors of NRF2: a review of their potential for clinical development. Oxid Med Cell Longev. 2019;2019:9372182.
   PubMed Web of Science ®Google Scholar
• Cuadrado A, Rojo AI, Wells G, et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov. 2019;18:295–317.
   PubMed Web of Science ®Google Scholar
• Cuadrado A, Manda G, Hassan A, et al. Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach. Pharmacol Rev. 2018;70:348–383.
   PubMed Web of Science ®Google Scholar
• Lynch DR, Farmer J, Hauser L, et al. Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia. Ann Clin Trans Neurol. 2019;6:15–26.
   PubMed Web of Science ®Google Scholar
• Rabbani PS, Ellison T, Waqas B, et al. Targeted Nrf2 activation therapy with RTA 408 enhances regenerative capacity of diabetic wounds. Diabetes Res Clin Pract. 2018;139:11–23.
   PubMed Web of Science ®Google Scholar
• Mou Y. CDDO-Me derivative, preparation method and medical application. CN108440636A. 2018.
   Google Scholar
• Cheng Y, Gong Y, Qian S, et al. Identification of a novel hybridization from Isosorbide 5-Mononitrate and bardoxolone methyl with dual activities of pulmonary vasodilation and vascular remodeling inhibition on pulmonary arterial hypertension rats. J Med Chem. 2018;61:1474–1482.
   PubMed Web of Science ®Google Scholar
• Huang Z, Mou Y, Xu X, et al. Novel derivative of bardoxolone methyl improves safety for the treatment of diabetic nephropathy. J Med Chem. 2017;60:8847–8857.
   PubMed Web of Science ®Google Scholar
• Kang F, Ai Y, Zhang Y, et al. Design and synthesis of new hybrids from 2-cyano-3,12-dioxooleana-9-dien-28-oic acid and O-2-(2,4-dinitrophenyl) diazeniumdiolate for intervention of drug-resistant lung cancer. Eur J Med Chem. 2018;149:269–280.
   PubMed Web of Science ®Google Scholar
• Woo SY, Kim JH, Moon MK, et al. Discovery of vinyl sulfones as a novel class of neuroprotective agents toward Parkinson’s disease therapy. J Med Chem. 2014;57:1473–1487.
   PubMed Web of Science ®Google Scholar
• Kim D, Park K, Park W, et al. Benzyl derivative compound containing activated vinyl group capable of being used for preventing and treating neurological disorders through nitric oxide generation inhibition and nrf2 activation, and pharmaceutical composition thereof. WO2013165140. 2013.
   Google Scholar
• Choi JW, Kim S, Park JH, et al. Optimization of vinyl sulfone derivatives as potent nuclear factor Erythroid 2-Related Factor 2 (Nrf2) activators for Parkinson’s disease therapy. J Med Chem. 2019;62:811–830.
   PubMed Web of Science ®Google Scholar
• Choi JW, Shin SJ, Kim HJ, et al. Antioxidant, anti-inflammatory, and neuroprotective effects of novel vinyl sulfonate compounds as Nrf2 activator. ACS Med Chem Lett. 2019;10:1061–1067.
   PubMed Web of Science ®Google Scholar
• Li A-L, Shen T, Wan T, et al. Novel diterpenoid-type activators of the Keap1/Nrf2/ARE signaling pathway and their regulation of redox homeostasis. Free Radic Biol Med. 2019;141:21–33.
   PubMed Web of Science ®Google Scholar
• Zhou M-X, Li G-H, Sun B, et al. Identification of novel Nrf2 activators from Cinnamomum chartophyllum HW Li and their potential application of preventing oxidative insults in human lung epithelial cells. Redox Bio. 2018;14:154–163.
   PubMed Web of Science ®Google Scholar
• Arbeeny CM, Ling H, Smith MM, et al. CXA-10, a nitrated fatty acid, is renoprotective in deoxycorticosterone acetate-salt nephropathy. J Pharmacol Exp Ther. 2019;369:503-+.
   PubMed Web of Science ®Google Scholar
• Bartholomeus J, Burli R, Jarvis R, et al. Small molecule modulators of the BTB domain of Keap1. WO2019122265. 2019.
   Google Scholar
• Wang L, Wang YR, Chen X, et al. Nrf2 activator compound, drugs and new application of atractylenolide II. CN106265633. 2017.
   Google Scholar
• George CA, Edward L, Stuart LB Tetrahydronaphthalene derivatives useful as Nrf2 activators. WO2019104030. 2019.
   Google Scholar
• Abed DA, Goldstein M, Albanyan H, et al. Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents. Acta Pharm Sin B. 2015;5:285–299.
   PubMed Web of Science ®Google Scholar
• Zhuang C, Miao Z, Sheng C, et al. Updated research and applications of small molecule inhibitors of Keap1-Nrf2 protein-protein interaction: a review. Curr Med Chem. 2014;21:1861–1870.
   PubMed Web of Science ®Google Scholar
• Leung CH, Zhang JT, Yang GJ, et al. Emerging screening approaches in the development of Nrf2-Keap1 protein-protein interaction inhibitors. Int J Mol Sci. 2019;20:4445.
   Web of Science ®Google Scholar
• Hoerer S, Reinert D, Ostmann K, et al. Crystal-contact engineering to obtain a crystal form of the Kelch domain of human Keap1 suitable for ligand-soaking experiments. Acta Crystallogr F. 2013;69:592–596.
   PubMedGoogle Scholar
• Padmanabhan B, Tong KI, Ohta T, et al. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell. 2006;21:689–700.
   PubMed Web of Science ®Google Scholar
• Beamer LJ, Li XC, Bottoms CA, et al. Conserved solvent and side-chain interactions in the 1.35 angstrom structure of the Kelch domain of Keap1. Acta Crystallogr D. 2005;61:1335–1342.
   PubMedGoogle Scholar
• Jiang ZY, Xu LL, Lu MC, et al. Investigation of the intermolecular recognition mechanism between the E3 ubiquitin ligase Keap1 and substrate based on multiple substrates analysis. J Comput Aided Mol Des. 2014;28:1233–1245.
   PubMed Web of Science ®Google Scholar
• Fukutomi T, Takagi K, Mizushima T, et al. Kinetic, thermodynamic, and structural characterizations of the association between Nrf2-DLGex degron and Keap1. Mol Cell Biol. 2014;34:832–846.
   PubMed Web of Science ®Google Scholar
• Lu MC, Jiao Q, Liu T, et al. Discovery of a head-to-tail cyclic peptide as the Keapl-Nrf2 protein-protein interaction inhibitor with high cell potency. Eur J Med Chem. 2018;143:1578–1589.
   PubMed Web of Science ®Google Scholar
• Lu MC, Yuan ZW, Jiang YL, et al. A systematic molecular dynamics approach to the study of peptide Keap1-Nrf2 protein-protein interaction inhibitors and its application to p62 peptides. Mol Biosyst. 2016;12:1378–1387.
   PubMedGoogle Scholar
• Hancock R, Schaap M, Pfister H, et al. Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction with improved binding and cellular activity. Org Biomol Chem. 2013;11:3553–3557.
   PubMed Web of Science ®Google Scholar
• Inoyama D, Chen Y, Huang X, et al. Optimization of fluorescently labeled Nrf2 peptide probes and the development of a fluorescence polarization assay for the discovery of inhibitors of Keap1-Nrf2 Interaction. J Biomol Screen. 2012;17:435–447.
   PubMed Web of Science ®Google Scholar
• Hancock R, Bertrand HC, Tsujita T, et al. Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction. Free Radic Biol Med. 2012;52:444–451.
   PubMed Web of Science ®Google Scholar
• Marcotte D, Zeng W, Hus J-C, et al. Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism. Biorg Med Chem. 2013;21:4011–4019.
   PubMed Web of Science ®Google Scholar
• Jiang ZY, Lu MC, Xu LL, et al. Discovery of potent Keap1-Nrf2 protein-protein interaction inhibitor based on molecular binding determinants analysis. J Med Chem. 2014;57:2736–2745.
   PubMed Web of Science ®Google Scholar
• Jiang ZY, Xu LL, Lu MC, et al. Structure-activity and structure-property relationship and exploratory in vivo evaluation of the nanomolar Keap1-Nrf2 protein-protein interaction inhibitor. J Med Chem. 2015;58:6410–6421.
   PubMed Web of Science ®Google Scholar
• Jain AD, Potteti H, Richardson BG, et al. Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators. Eur J Med Chem. 2015;103:252–268.
   PubMed Web of Science ®Google Scholar
• Lu MC, Zhao J, Liu YT, et al. CPUY192018, a potent inhibitor of the Keap1-Nrf2 protein-protein interaction, alleviates renal inflammation in mice by restricting oxidative stress and NF-kappaB activation. Redox Biol. 2019;26:101266.
   PubMed Web of Science ®Google Scholar
• Hui Q, Karlstetter M, Xu Z, et al. Inhibition of the Keap1-Nrf2 protein-protein interaction protects retinal cells and ameliorates retinal ischemia-reperfusion injury. Free Radic Biol Med. 2019;146:181–188.
   Web of Science ®Google Scholar
• Lu MC, Zhang X, Wu F, et al. Discovery of a potent Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1-Nrf2) protein-protein interaction inhibitor with natural proline structure as a cytoprotective agent against acetaminophen-induced hepatotoxicity. J Med Chem. 2019;62:6796–6813.
   PubMed Web of Science ®Google Scholar
• You QD, Jiang ZY, Tan SJ, et al. Naphthyl sulfamide amino acid derivative, preparation method and medical application thereof. CN108101821. 2018.
   Google Scholar
• Richardson BG, Jain AD, Potteti HR, et al. Replacement of a naphthalene scaffold in Kelch-like ECH-Associated Protein 1 (KEAP1)/Nuclear Factor (Erythroid-derived 2)-like 2 (NRF2) Inhibitors. J Med Chem. 2018;61:8029–8047.
   PubMed Web of Science ®Google Scholar
• Winkel AF, Engel CK, Margerie D, et al. Characterization of RA839, a noncovalent small molecule binder to Keap1 and selective activator of Nrf2 signaling. J Biol Chem. 2015;290:28446–28455.
   PubMed Web of Science ®Google Scholar
• Schwarz LR, Mezger M, Hesse S. Effect of decreased glucuronidation and sulfation on covalent binding of naphthalene in isolated rat hepatocytes. Toxicology. 1980;17:119–122.
   PubMed Web of Science ®Google Scholar
• Buckpitt A, Boland B, Isbell M, et al. Naphthalene-induced respiratory tract toxicity: metabolic mechanisms of toxicity. Drug Metab Rev. 2002;34:791–820.
   PubMed Web of Science ®Google Scholar
• Tsuruda LS, Lame MW, Jones AD. Formation of epoxide and quinone protein adducts in B6C3F1 mice treated with naphthalene, sulfate conjugate of 1,4-dihydroxynaphthalene and 1,4-naphthoquinone. Arch Toxicol. 1995;69:362–367.
   PubMed Web of Science ®Google Scholar
• Buckpitt AR, Warren DL. Evidence for hepatic formation, export and covalent binding of reactive naphthalene metabolites in extrahepatic tissues in vivo. J Pharmacol Exp Ther. 1983;225:8–16.
   PubMed Web of Science ®Google Scholar
• Hsu KH, Su BH, Tu YS, et al. Mutagenicity in a molecule: identification of core structural features of mutagenicity using a scaffold analysis. PLoS One. 2016;11(2):e0148900.
   Web of Science ®Google Scholar
• Bulbulyan MA, Figgs LW, Zahm SH, et al. Cancer incidence and mortality among beta-naphthylamine and benzidine dye workers in Moscow. Int J Epidemiol. 1995;24:266–275.
   PubMed Web of Science ®Google Scholar
• Saito T, Ichimura Y, Taguchi K, et al. p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming. Nat Commun. 2016;7:12030.
   PubMed Web of Science ®Google Scholar
• Yasuda D, Nakajima M, Yuasa A, et al. Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity. Bioorg Med Chem Lett. 2016;26:5956–5959.
   PubMed Web of Science ®Google Scholar
• Yasuda D, Yuasa A, Obata R, et al. Discovery of benzo g indoles as a novel class of non-covalent Keap1-Nrf2 protein-protein interaction inhibitor. Bioorg Med Chem Lett. 2017;27:5006–5009.
   PubMed Web of Science ®Google Scholar
• Tran KT, Pallesen JS, Solbak SMO, et al. A comparative assessment study of known small-molecule Keap1-Nrf2 protein-protein interaction inhibitors: chemical synthesis, binding properties, and cellular activity. J Med Chem. 2019;62:8028–8052.
   PubMed Web of Science ®Google Scholar
• Hu L, Magesh S, Chen L, et al. Direct inhibitors of Keap1-Nrf2 interaction as antioxidant inflammation modulators. WO2013067036. 2018.
   Google Scholar
• Meng N, Tang H, Zhang H, et al. Fragment-growing guided design of Keap1-Nrf2 protein-protein interaction inhibitors for targeting myocarditis. Free Radic Biol Med. 2018;117:228–237.
   PubMed Web of Science ®Google Scholar
• Dahlin JL, Inglese J, Walters MA. Mitigating risk in academic preclinical drug discovery. Nat Rev Drug Discov. 2015;14:279–294.
   PubMed Web of Science ®Google Scholar
• Davies TG, Wixted WE, Coyle JE, et al. Monoacidic inhibitors of the Kelch-like ECH-Associated Protein 1: nuclear factor Erythroid 2-Related Factor 2 (KEAP1: NRF2)protein protein interaction with high cell potency identified by fragment-based discovery. J Med Chem. 2016;59:3991–4006.
   PubMed Web of Science ®Google Scholar
• Boehm JC, Davies TG, Woolford -AJ-A, et al. Preparation of sulfonylamino phenyl propanoic acid derivatives as Nrf2 regulators. WO2015092713. 2015.
   Google Scholar
• Boehm JC, Davies TG, Woolford -AJ-A, et al. Nrf2 regulators. US2019002454. 2019.
   Google Scholar
• Matthews JM Nrf2 Compounds. WO2018109646. 2018.
   Google Scholar
• Heightman TD, Callahan JF, Chiarparin E, et al. Structure-activity and structure-conformation relationships of Aryl propionic acid inhibitors of the Kelch-like ECH-associated protein 1/Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1/NRF2) protein-protein interaction. J Med Chem. 2019;62:4683–4702.
   PubMed Web of Science ®Google Scholar
• Callahan JF, Kerns JJ, Li T, et al. Biaryl pyrazoles as Nrf2 regulators. WO2017060854. 2017.
   Google Scholar
• Callahan JF, Kerns JJ, Li T, et al. Arylcyclohexyl pyrazoles as Nrf2 regulators. WO2017060855. 2017.
   Google Scholar
• Xu LL, Zhu JF, Xu XL, et al. Discovery and modification of in vivo active Nrf2 Activators with 1,2,4-Oxadiazole Core: hits identification and structure-activity relationship study. J Med Chem. 2015;58:5419–5436.
   PubMed Web of Science ®Google Scholar
• Xu LL, Liu T, Wang L, et al. 3-(1H-Benzo d imidazol-6-yl)-5-(4-fluorophenyl)-1,2,4-oxadiazole (DDO7232), a Novel Potent Nrf2/ARE Inducer, Ameliorates DSS-Induced Murine Colitis and Protects NCM460 Cells against Oxidative Stress via ERK1/2 Phosphorylation. Oxid Med Cell Longev. 2018;2018:3271617.
   Web of Science ®Google Scholar
• Xu LL, Zhang X, Jiang ZY, et al. Molecular similarity guided optimization of novel Nrf2 activators with 1,2,4-oxadiazole core. Biorg Med Chem. 2016;24:3540–3547.
   PubMed Web of Science ®Google Scholar
• Xu LL, Wu YF, Wang L, et al. Structure-activity and structure-property relationships of novel Nrf2 activators with a 1,2,4-oxadiazole core and their therapeutic effects on acetaminophen (APAP)-induced acute liver injury. Eur J Med Chem. 2018;157:1376–1394.
   PubMed Web of Science ®Google Scholar
• Xu LL, Wu YF, Yan F, et al. 5-(3,4-Difluorophenyl)-3-(6-methylpyridin-3-yl)-1,2,4-oxadiazole (DDO-7263), a novel Nrf2 activator targeting brain tissue, protects against MPTP-induced subacute Parkinson’s disease in mice by inhibiting the NLRP3 inflammasome and protects PC12 cells against oxidative stress. Free Radic Biol Med. 2019;134:288–303.
   PubMed Web of Science ®Google Scholar
• Zheng S, Laxmi YRS, David E, et al. Synthesis, Chemical Reactivity as Michael Acceptors, and Biological Potency of Monocyclic Cyanoenones, Novel and Highly Potent Anti-inflammatory and Cytoprotective Agents. J Med Chem. 2012;55:4837–4846.
   PubMed Web of Science ®Google Scholar
• Bradshaw JM, McFarland JM, Paavilainen VO, et al. Prolonged and tunable residence time using reversible covalent kinase inhibitors. Nat Chem Biol. 2015;11:525-+.
   PubMed Web of Science ®Google Scholar
• Mazzuferi M, Kumar G, van Eyll J, et al. Nrf2 Defense Pathway: experimental Evidence for Its Protective Role in Epilepsy. Ann Neurol. 2013;74:560–568.
   PubMed Web of Science ®Google Scholar
• Gao B, Doan A, Hybertson BM. The clinical potential of influencing Nrf2 signaling in degenerative and immunological disorders. Clin Pharmacol. 2014;6:19–34.
   PubMedGoogle Scholar
• Sivandzade F, Prasad S, Bhalerao A, et al. NRF2 and NF-B interplay in cerebrovascular and neurodegenerative disorders: molecular mechanisms and possible therapeutic approaches. Redox Biol. 2019;21:101059.
   PubMed Web of Science ®Google Scholar
• Sheng C, Dong G, Miao Z, et al. State-of-the-art strategies for targeting protein-protein interactions by small-molecule inhibitors. Chem Soc Rev. 2015;44:8238–8259.
   PubMed Web of Science ®Google Scholar
• Lu MC, Tan SJ, Ji JA, et al. Polar Recognition Group Study of Keap1-Nrf2 Protein-Protein Interaction Inhibitors. ACS Med Chem Lett. 2016;7:835–840.
   PubMed Web of Science ®Google Scholar
• Jiang ZY, Lu MC, You QD. Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Inhibition: an Emerging Strategy in Cancer Therapy. J Med Chem. 2019;62:3840–3856.
   PubMed Web of Science ®Google Scholar
• Rojo de la Vega M, Chapman E, Zhang DD. NRF2 and the Hallmarks of Cancer. Cancer Cell. 2018;34:21–43.
   PubMed Web of Science ®Google Scholar
• Menegon S, Columbano A, Giordano S. The Dual Roles of NRF2 in Cancer. Trends Mol Med. 2016;22:578–593.
   PubMed Web of Science ®Google Scholar
• Pakpoor J, Disanto G, Altmann DR, et al. No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine. Neurol Neuroimmunol Neuroinflamm. 2015;2:158.
   PubMed Web of Science ®Google Scholar