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Nrf2 activation through the inhibition of Keap1–Nrf2 protein–protein interaction

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Abstract

Activation of the transcription factor Nrf2 via the Keap1–Nrf2–ARE signaling system regulates the transcription and subsequent expression of cellular cytoprotective proteins and plays a crucial role in preventing pathological conditions exacerbated by the overproduction of oxidative stress. In addition to electrophilic modulators, direct noncovalent inhibitors that interrupt the Keap1–Nrf2 protein–protein interaction (PPI) leading to Nrf2 activation have attracted a great deal of attention as potential preventive and therapeutic agents for oxidative stress-related diseases. Structural studies of Keap1-binding ligands, development of biochemical and cellular assays, and new structure-based design approaches have facilitated the discovery of small molecule PPI inhibitors. This perspective reviews the Keap1–Nrf2–ARE system, its physiological functions, and the recent progress in the discovery and the potential applications of direct inhibitors of Keap1–Nrf2 PPI.

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Abbreviations

AD:

Alzheimer’s disease

ALS:

amyotrophic lateral sclerosis

ARE:

antioxidant response element

BTB:

broad-complex, Tramtrack and Bric-a-Brac

bZip:

leucine zipper

CBP:

CREB-binding protein

CDDO-Me:

bardoxolone methyl

CKD:

chronic kidney disease

COPD:

chronic obstructive pulmonary disease

Cul3:

cullin3

2D-FIDA:

two-dimensional fluorescence intensity distribution analysis

DGR:

double glycine repeat

FBDD:

fragment-based drug discovery

DMF:

dimethyl fumarate

FA:

fluorescence anisotropy

FITC:

fluorescein isothiocyanate

FP:

fluorescence polarization

GCL:

glutamate–cysteine ligase

GCLC:

glutamate–cysteine ligase catalytic

GCLM:

glutamate–cysteine ligase modifier

GPx:

glutathione peroxidase

GST:

glutathione S-transferase

HD:

Huntington’s disease

HMOX1:

heme oxygenase 1

HO-1:

heme oxygenase 1

HTS:

high-throughput screening

ITC:

isothermal titration calorimetry assay

IVR:

intervening region

Keap1:

Kelch-like ECH-associated protein 1

Maf:

musculoaponeurotic fibrosarcoma protein

MD:

molecular dynamics

MM-GBSA:

molecular mechanics-generalized Born surface area

MS:

multiple sclerosis

NADPH:

Nicotinamide adenine dinucleotide phosphate

Neh:

Nrf2–ECH homology

NQO1:

NAD(P)H:quinone oxidoreductase 1

NFE2:

nuclear factor, erythroid-derived 2

Nrf2:

nuclear factor erythroid 2-related factor 2

PD:

Parkinson’s disease

PDB:

Protein Data Bank

PPI:

protein−protein interaction

Rbx1:

RING-box protein 1

qRT-PCR:

quantitative real-time polymerase chain reaction

RNS:

reactive nitrogen species

ROS:

reactive oxygen species

SAR:

structure–activity relationship

sMaf:

small musculoaponeurotic fibrosarcoma protein

SOD:

superoxide dismutase

SPR:

surface plasmon resonance

THIQ:

tetrahydroisoquinoline

TR-FRET:

time-resolved fluorescence (or Förster) resonance energy transfer

TRX:

thioredoxin

References

  • Abed DA, Goldstein M, Albanyan H, Jin H, Hu L (2015) Discovery of direct inhibitors of Keap1–Nrf2 protein–protein interaction as potential therapeutic and preventive agents. Acta Pharm Sin B 5:285–299

    Article  PubMed  PubMed Central  Google Scholar 

  • Abed DA, Lee S, Hu L (2020) Discovery of disubstituted xylylene derivatives as small molecule direct inhibitors of Keap1-Nrf2 protein-protein interaction. Bioorg Med Chem 28:115343

    Article  CAS  PubMed  Google Scholar 

  • Arkin Michelle R, Tang Y, Wells James A (2014) Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chem Biol 21:1102–1114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baird L, Llères D, Swift S, Dinkova-Kostova AT (2013) Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex. Proc Natl Acad Sci USA 110:15259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baird L, Swift S, Llères D, Dinkova-Kostova AT (2014) Monitoring Keap1–Nrf2 interactions in single live cells. Biotechnol Adv 32:1133–1144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bertrand HC, Schaap M, Baird L, Georgakopoulos ND, Fowkes A, Thiollier C, Kachi H, Dinkova-Kostova AT, Wells G (2015) Design, synthesis, and evaluation of triazole derivatives that induce Nrf2 dependent gene products and inhibit the Keap1–Nrf2 protein–protein interaction. J Med Chem 58:7186–7194

    Article  CAS  PubMed  Google Scholar 

  • Blundell TL, Burke DF, Chirgadze D, Dhanaraj V, Hyvonen M, Innis CA, Parisini E, Pellegrini L, Sayed M, Sibanda BL (2000) Protein-protein interactions in receptor activation and intracellular signalling. Biol Chem 381:955–959

    Article  CAS  PubMed  Google Scholar 

  • Boerboom A-MJF, Vermeulen M, van der Woude H, Bremer BI, Lee-Hilz YY, Kampman E, van Bladeren PJ, Rietjens IMCM, Aarts JMMJG (2006) Newly constructed stable reporter cell lines for mechanistic studies on electrophile-responsive element-mediated gene expression reveal a role for flavonoid planarity. Biochem Pharm 72:217–226

    Article  CAS  PubMed  Google Scholar 

  • Boutten A, Goven D, Artaud-Macari E, Boczkowski J, Bonay M (2011) NRF2 targeting: a promising therapeutic strategy in chronic obstructive pulmonary disease. Trends Mol Med 17:363–371

    Article  CAS  PubMed  Google Scholar 

  • Calkins MJ, Jakel RJ, Johnson DA, Chan K, Kan YW, Johnson JA (2005) Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription. Proc Natl Acad Sci USA 102:244

    Article  CAS  PubMed  Google Scholar 

  • Callahan JF, Kerns JJ, Li T, Nie H, Pero JE, Davies TG, Heightman TD, Woolford AJ, Griffiths-Jones CM, Norton D, Verdonk ML, Howard S (2017a) Arylcyclohexyl pyrazoles as Nrf2 regulators. WO2017060855

  • Callahan JF, Kerns JJ, Li T, Nie H, Pero JE, Davies TG, Heightman TD, Woolford A, Griffiths-Jones CM, Norton D, Willems HMG, Verdonk ML, Carr MG (2017b) Biaryl pyrazoles as Nrf2 regulators. WO2017060854

  • Canning P, Sorrell FJ, Bullock AN (2015) Structural basis of Keap1 interactions with Nrf2. Free Radic Biol Med 88:101–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chabas SA, Jiang Q, McMahon M, McWalter GK, McLellan LI, Elcombe CR, Henderson CJ, Wolf CR, Moffat GJ, Itoh K, Yamamoto M, Hayes JD (2002) Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and inducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3 and Gstm4 genes in the livers of male and female mice. Biochem J 365:405–416

    Article  Google Scholar 

  • Chen P-C, Vargas MR, Pani AK, Smeyne RJ, Johnson DA, Kan YW, Johnson JA (2009) Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson’s disease: Critical role for the astrocyte. Proc Natl Acad Sci USA 106:2933–2938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Y, Inoyama D, Kong A-NT, Beamer LJ, Hu L (2011) Kinetic analyses of Keap1–Nrf2 interaction and determination of the minimal Nrf2 peptide sequence required for Keap1 binding using surface plasmon resonance. Chem Biol Drug Des 78:1014–1021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cleasby A, Yon J, Day PJ, Richardson C, Tickle IJ, Williams PA, Callahan JF, Carr R, Concha N, Kerns JK, Qi H, Sweitzer T, Ward P, Davies TG (2014) Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO. PLoS ONE 9:e98896

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Davies TG, Wixted WE, Coyle JE, Griffiths-Jones C, Hearn K, McMenamin R, Norton D, Rich SJ, Richardson C, Saxty G, Willems HMG, Woolford AJA, Cottom JE, Kou J-P, Yonchuk JG, Feldser HG, Sanchez Y, Foley JP, Bolognese BJ, Logan G, Podolin PL, Yan H, Callahan JF, Heightman TD, Kerns JK (2016) 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 59:3991–4006

    Article  CAS  PubMed  Google Scholar 

  • De Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, Goldsberry A, Houser M, Krauth M, Lambers Heerspink HJ (2013) Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N. Engl J Med 369:2492–2503

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dimmock JR, Elias DW, Beazely MA, Kandepu NM (1999) Bioactivities of chalcones. Curr Med Chem 6:1125–1149

    Article  CAS  PubMed  Google Scholar 

  • Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M, Talalay P (2002) 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 99:11908–11913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dinkova-Kostova AT, Holtzclaw WD, Kensler TW (2005) The role of Keap1 in cellular protective responses. Chem Res Toxicol 18:1779–1791

    Article  CAS  PubMed  Google Scholar 

  • Dinkova-Kostova AT, Wang XJ (2011) Induction of the Keap1/Nrf2/ARE pathway by oxidizable diphenols. Chem Biol Interact 192:101–106

    Article  CAS  PubMed  Google Scholar 

  • DiscoverX (2011) PathHunter® Keap1–Nrf2 functional assay for chemiluminescent detection of activated Nrf2. In. Product Booklet: 93-0821C3. https://www.discoverx.com/products/cell-line/u2os-keap1-nrf2-nuclear-translocation-ce-93-0821c3. Accessed 10 October 2012

  • Eggler A, Liu G, M Pezzuto J, van Breemen R, D Mesecar A (2005) Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2. Proc Natl Acad Sci USA 102:10070–10075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eggler Aimee L, Small E, Hannink M, Mesecar Andrew D (2009) Cul3-mediated Nrf2 ubiquitination and antioxidant response element (ARE) activation are dependent on the partial molar volume at position 151 of Keap1. Biochem J 422:171–180

    Article  CAS  PubMed  Google Scholar 

  • Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247

    Article  CAS  PubMed  Google Scholar 

  • Fujiwara KT, Kataoka K, Nishizawa M (1993) Two new members of the maf oncogene family, mafK and mafF, encode nuclear b-Zip proteins lacking putative trans-activator domain. Oncogene 8:2371–2380

    CAS  PubMed  Google Scholar 

  • Fukutomi T, Takagi K, Mizushima T, Ohuchi N, Yamamoto M (2014) Kinetic, thermodynamic, and structural characterizations of the association between Nrf2-DLGex degron and Keap1. Mol Cell Biol 34:832–846

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Geismann C, Arlt A, Sebens S, Schäfer H (2014) Cytoprotection “gone astray”: Nrf2 and its role in cancer. Onco Targets Ther 7:1497–1518

    PubMed  PubMed Central  Google Scholar 

  • Go ML, Wu X, Liu XL (2005) Chalcones: an update on cytotoxic and chemoprotective properties. Curr Med Chem 12:481–499

    Article  CAS  PubMed  Google Scholar 

  • Golden TR, Patel M (2008) Catalytic antioxidants and neurodegeneration. Antioxid Redox Signal 11:555–569

    Article  CAS  Google Scholar 

  • Hall MD, Yasgar A, Peryea T, Braisted JC, Jadhav A, Simeonov A, Coussens NP (2016) Fluorescence polarization assays in high-throughput screening and drug discovery: a review. Methods Appl Fluoresc 4:022001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hayes JD, McMahon M, Chowdhry S, Dinkova-Kostova AT (2010) Cancer chemoprevention mechanisms mediated through the Keap1–Nrf2 pathway. Antioxid Redox Signal 13:1713–1748

    Article  CAS  PubMed  Google Scholar 

  • He X, Ma Q (2010) Critical cysteine residues of Kelch-like ECH-associated protein 1 in arsenic sensing and suppression of nuclear factor erythroid 2-related factor 2. J Pharm Exp Ther 332:66–75

    Article  CAS  Google Scholar 

  • Heightman TD, Callahan JF, Chiarparin E, Coyle JE, Griffiths-Jones C, Lakdawala AS, McMenamin R, Mortenson PN, Norton D, Peakman TM, Rich SJ, Richardson C, Rumsey WL, Sanchez Y, Saxty G, Willems HMG, Wolfe L, Woolford AJA, Wu Z, Yan H, Kerns JK, Davies TG (2019) 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 62:4683–4702

    Article  CAS  PubMed  Google Scholar 

  • Honda T, Rounds BV, Gribble GW, Suh N, Wang Y, Sporn MB (1998) Design and synthesis of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, a novel and highly active inhibitor of nitric oxide production in mouse macrophages. Bioorg Med Chem Lett 8:2711–2714

    Article  CAS  PubMed  Google Scholar 

  • Hong F, Freeman ML, Liebler DC (2005) Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chem Res Toxicol 18:1917–1926

    Article  CAS  PubMed  Google Scholar 

  • Hu L, Magesh S, Chen L, Lewis T, Munoz B, Wang L (2013a) Direct inhibitors of Keap1-Nrf2 interaction as antioxidant inflammation modulators. WO2013067036 A1

  • Hu L, Magesh S, Chen L, Wang L, Lewis TA, Chen Y, Khodier C, Inoyama D, Beamer LJ, Emge TJ, Shen J, Kerrigan JE, Kong AN, Dandapani S, Palmer M, Schreiber SL, Munoz B (2013b) Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction. Bioorg Med Chem Lett 23:3039–3043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ighodaro OM, Akinloye OA (2018) First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): their fundamental role in the entire antioxidant defence grid. Alex J Med 54:287–293

    Google Scholar 

  • Iizuka T, Ishii Y, Itoh K, Kiwamoto T, Kimura T, Matsuno Y, Morishima Y, Hegab AE, Homma S, Nomura A, Sakamoto T, Shimura M, Yoshida A, Yamamoto M, Sekizawa K (2005) Nrf2-deficient mice are highly susceptible to cigarette smoke-induced emphysema. Genes Cells 10:1113–1125

    Article  CAS  PubMed  Google Scholar 

  • Inoyama D, Chen Y, Huang X, Beamer LJ, Kong A-NT, Hu L (2012) 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 17:435–447

    Article  CAS  PubMed  Google Scholar 

  • Ishii Y, Itoh K, Morishima Y, Kimura T, Kiwamoto T, Iizuka T, Hegab AE, Hosoya T, Nomura A, Sakamoto T, Yamamoto M, Sekizawa K (2005) Transcription factor Nrf2 plays a pivotal role in protection against elastase-induced pulmonary inflammation and emphysema. J Immunol 175:6968–6975

    Article  CAS  PubMed  Google Scholar 

  • Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y-i (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236:313–322

    Article  CAS  PubMed  Google Scholar 

  • Itoh K, Mimura J, Yamamoto M (2010) Discovery of the negative regulator of Nrf2, Keap1: a historical overview. Antioxid Redox Signal 13:1665–1678

    Article  CAS  PubMed  Google Scholar 

  • Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13:76–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jain AD, Potteti H, Richardson BG, Kingsley L, Luciano JP, Ryuzoji AF, Lee H, Krunic A, Mesecar AD, Reddy SP, Moore TW (2015) Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators. Eur J Med Chem 103:252–268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang C-S, Zhuang C-L, Zhu K, Zhang J, Muehlmann LA, Figueiró Longo JP, Azevedo RB, Zhang W, Meng N, Zhang H (2018) Identification of a novel small-molecule Keap1–Nrf2 PPI inhibitor with cytoprotective effects on LPS-induced cardiomyopathy. J Enzym Inhib Med Chem 33:833–841

    Article  CAS  Google Scholar 

  • Jiang ZY, Lu MC, Xu LL, Yang TT, Xi MY, Xu XL, Guo XK, Zhang XJ, You QD, Sun HP (2014b) Discovery of potent Keap1-Nrf2 protein-protein interaction inhibitor based on molecular binding determinants analysis. J Med Chem 57:2736–2745

    Article  CAS  PubMed  Google Scholar 

  • Jiang Z-Y, Lu M-C, You Q-D (2016) 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 59:10837–10858

    Article  CAS  PubMed  Google Scholar 

  • Jiang Z-Y, Xu LL, Lu M-C, Chen Z-Y, Yuan Z-W, Xu X-L, Guo X-K, Zhang X-J, Sun H-P, You Q-D (2015) Structure–activity and structure–property relationship and exploratory in vivo evaluation of the nanomolar Keap1–Nrf2 protein–protein interaction inhibitor. J Med Chem 58:6410–6421

    Article  CAS  PubMed  Google Scholar 

  • Jiang Z-Y, Xu L-L, Lu M-C, Pan Y, Huang H-Z, Zhang X-J, Sun H-P, You Q-D (2014a) Investigation of the intermolecular recognition mechanism between the E3 ubiquitin ligase Keap1 and substrate based on multiple substrates analysis. J Comput Aided Mol Des 28:1233–1245

    Article  CAS  PubMed  Google Scholar 

  • Jiménez-Osorio AS, Picazo A, González-Reyes S, Barrera-Oviedo D, Rodríguez-Arellano ME, Pedraza-Chaverri J (2014) Nrf2 and redox status in prediabetic and diabetic patients. Int J Mol Sci 15:20290–20305

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jnoff E, Albrecht C, Barker JJ, Barker O, Beaumont E, Bromidge S, Brookfield F, Brooks M, Bubert C, Ceska T (2014) Binding mode and structure–activity relationships around direct inhibitors of the Nrf2–Keap1 complex. ChemMedChem 9:699–705

    Article  CAS  PubMed  Google Scholar 

  • Johnson DA, Amirahmadi S, Ward C, Fabry Z, Johnson JA (2009) The absence of the pro-antioxidant transcription factor Nrf2 exacerbates experimental autoimmune encephalomyelitis. Toxicol Sci 114:237–246

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kansanen E, Kuosmanen SM, Leinonen H, Levonen A-L (2013) The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Redox Biol 1:45–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katoh Y, Iida K, Kang M-I, Kobayashi A, Mizukami M, Tong KI, McMahon M, Hayes JD, Itoh K, Yamamoto M (2005) Evolutionary conserved N-terminal domain of Nrf2 is essential for the Keap1-mediated degradation of the protein by proteasome. Arch Biochem Biophys 433:342–350

    Article  CAS  PubMed  Google Scholar 

  • Katoh Y, Itoh K, Yoshida E, Miyagishi M, Fukamizu A, Yamamoto M (2001) Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells 6:857–868

    Article  CAS  PubMed  Google Scholar 

  • Katsuoka F, Motohashi H, Ishii T, Aburatani H, Engel JD, Yamamoto M (2005) Genetic evidence that small maf proteins are essential for the activation of antioxidant response element-dependent genes. Mol Cell Biol 25:8044–8051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kazantsev AG, Thompson LM, Abagyan R, Casale M (2014) Small molecule activators of Nrf2 pathway. WO2014197818A2

  • Kensler TW, Wakabayashi N (2009) Nrf2: friend or foe for chemoprevention? Carcinogenesis 31:90–99

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Khor TO, Huang M-T, Kwon KH, Chan JY, Reddy BS, Kong A-N (2006) Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium–induced colitis. Cancer Res 66:11580–11584

    Article  CAS  PubMed  Google Scholar 

  • Kirkham PA, Barnes PJ (2013) Oxidative stress in COPD. Chest 144:266–273

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi A, Kang M-I, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M (2004) Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol 24:7130–7139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar V, Kumar S, Hassan M, Wu H, Thimmulappa RK, Kumar A, Sharma SK, Parmar VS, Biswal S, Malhotra SV (2011) Novel chalcone derivatives as potent Nrf2 activators in mice and human lung epithelial cells. J Med Chem 54:4147–4159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kurzawski M, Dziedziejko V, Urasińska E, Post M, Wójcicki M, Miętkiewski J, Droździk M (2012) Nuclear factor erythroid 2-like 2 (Nrf2) expression in end-stage liver disease. Environ Toxicol Pharm 34:87–95

    Article  CAS  Google Scholar 

  • Lazzara PR, David BP, Ankireddy A, Richardson BG, Dye K, Ratia KM, Reddy SP, Moore TW (2020) Isoquinoline Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2 (KEAP1-NRF2) inhibitors with high metabolic stability. J Med Chem ASAP. https://doi.org/10.1021/acs.jmedchem.1029b01074

  • Lea WA, Simeonov A (2011) Fluorescence polarization assays in small molecule screening. Expert Opin Drug Discov 6:17–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee D-H, Gold R, Linker RA (2012) Mechanisms of oxidative damage in multiple sclerosis and neurodegenerative diseases: therapeutic modulation via fumaric acid esters. Int J Mol Sci 13:11783–11803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee J-M, Johnson JA (2004) An important role of Nrf2-ARE pathway in the cellular defense mechanism. J Biochem Mol Biol 37:139–143

    CAS  PubMed  Google Scholar 

  • Li J, Ichikawa T, Janicki JS, Cui T (2009) Targeting the Nrf2 pathway against cardiovascular disease. Expert Opin Ther Targets 13:785–794

    Article  CAS  PubMed  Google Scholar 

  • Li J, Johnson D, Calkins M, Wright L, Svendsen C, Johnson J (2004a) Stabilization of Nrf2 by tBHQ confers protection against oxidative stress-induced cell death in human neural stem cells. Toxicol Sci 83:313–328

    Article  PubMed  Google Scholar 

  • Li X, Zhang D, Hannink M, Beamer LJ (2004b) Crystal structure of the Kelch domain of human Keap1. J Biol Chem 279:54750–54758

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Paonessa JD, Zhang Y (2012) Mechanism of chemical activation of Nrf2. PLoS ONE 7:e35122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liby KT, Yore MM, Sporn MB (2007) Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat Rev Cancer 7:357–369

    Article  CAS  PubMed  Google Scholar 

  • Linker RA, Lee D-H, Ryan S, van Dam AM, Conrad R, Bista P, Zeng W, Hronowsky X, Buko A, Chollate S, Ellrichmann G, Brück W, Dawson K, Goelz S, Wiese S, Scannevin RH, Lukashev M, Gold R (2011) Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134:678–692

    Article  PubMed  Google Scholar 

  • Lo SC, Li X, Henzl MT, Beamer LJ, Hannink M (2006) Structure of the Keap1: Nrf2 interface provides mechanistic insight into Nrf2 signaling. EMBO J 25:3605–3617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu M-C, Chen Z-Y, Wang Y-L, Jiang Y-L, Yuan Z-W, You Q-D, Jiang Z-Y (2015) Binding thermodynamics and kinetics guided optimization of potent Keap1–Nrf2 peptide inhibitors. RSC Adv 5:85983–85987

    Article  CAS  Google Scholar 

  • Lu M-C, Tan S-J, Ji J-A, Chen Z-Y, Yuan Z-W, You Q-D, Jiang Z-Y (2016) Polar recognition group study of Keap1-Nrf2 protein–protein interaction inhibitors. ACS Med Chem Lett 7:835–840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu M-C, Zhang X, Wu F, Tan S-J, Zhao J, You Q-D, Jiang Z-Y (2019a) 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 62:6796–6813

    Article  CAS  PubMed  Google Scholar 

  • Lu M-C, Zhao J, Liu Y-T, Liu T, Tao M-M, You Q-D, Jiang Z-Y (2019b) CPUY192018, a potent inhibitor of the Keap1-Nrf2 protein-protein interaction, alleviates renal inflammation in mice by restricting oxidative stress and NF-κB activation. Redox Bio 26:101266

    Article  CAS  Google Scholar 

  • Ma Q (2013) Role of Nrf2 in oxidative stress and toxicity. Annu Rev Pharm Toxicol 53:401–426

    Article  CAS  Google Scholar 

  • Ma Q, Battelli L, Hubbs AF (2006) Multiorgan autoimmune inflammation, enhanced lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the antioxidant-activated transcription factor Nrf2. Am J Pathol 168:1960–1974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Magesh S, Chen Y, Hu L (2012) Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents. Med Res Rev 32:687–726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maicas N, Ferrándiz ML, Brines R, Ibáñez L, Cuadrado A, Koenders MI, van den Berg WB, Alcaraz MJ (2011) Deficiency of Nrf2 accelerates the effector phase of arthritis and aggravates joint disease. Antioxid Redox Signal 15:889–901

    Article  CAS  PubMed  Google Scholar 

  • Marcotte D, Zeng W, Hus J-C, McKenzie A, Hession C, Jin P, Bergeron C, Lugovskoy A, Enyedy I, Cuervo H, Wang D, Atmanene C, Roecklin D, Vecchi M, Vivat V, Kraemer J, Winkler D, Hong V, Chao J, Lukashev M, Silvian L (2013) Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism. Bioorg Med Chem 21:4011–4019

    Article  CAS  PubMed  Google Scholar 

  • McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD (2004) 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 279:31556–31567

    Article  CAS  PubMed  Google Scholar 

  • McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD (2006) Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a “tethering” mechanism: a two-site interaction model for the Nrf2-Keap1 complex. J Biol Chem 281:24756–24768

    Article  CAS  PubMed  Google Scholar 

  • Meng N, Tang H, Zhang H, Jiang C, Su L, Min X, Zhang W, Zhang H, Miao Z, Zhang W, Zhuang C (2018) Fragment-growing guided design of Keap1-Nrf2 protein-protein interaction inhibitors for targeting myocarditis. Free Radic Biol Med 117:228–237

    Article  CAS  PubMed  Google Scholar 

  • Moi P, Chan K, Asunis I, Cao A, Kan YW (1994) Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci USA 91:9926–9930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moon EJ, Giaccia A (2015) Dual roles of NRF2 in tumor prevention and progression: possible implications in cancer treatment. Free Radic Biol Med 79:292–299

    Article  CAS  PubMed  Google Scholar 

  • Mrowietz U, Altmeyer P, Bieber T, Röcken M, Schopf RE, Sterry W (2007) Treatment of psoriasis with fumaric acid esters (Fumaderm®). J Dtsch Dermatol Ges 5:716–717

    Article  PubMed  Google Scholar 

  • Nioi P, Nguyen T, Sherratt PJ, Pickett CB (2005) The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation. Mol Cell Biol 25:10895–10906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ogura T, Tong KI, Mio K, Maruyama Y, Kurokawa H, Sato C, Yamamoto M (2010) Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains. Proc Natl Acad Sci USA 107:2842–2847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pallesen JS, Tran KT, Bach A (2018) 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. J Med Chem 61:8088–8103

    Article  CAS  PubMed  Google Scholar 

  • Paul N, McMahon M, Ken I, Yamamoto M, Hayes JD (2003) Identification of a novel Nrf2-regulated antioxidant response element (ARE) in the mouse NAD (P) H: quinone oxidoreductase 1 gene: reassessment of the ARE consensus sequence. Biochem J 374:337–348

    Article  Google Scholar 

  • Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, Krauth M, Ruiz S, Audhya P, Christ-Schmidt H, Wittes J, Warnock DG (2011) Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N. Engl J Med 365:327–336

    Article  CAS  PubMed  Google Scholar 

  • Probst BL, McCauley L, Trevino I, Wigley WC, Ferguson DA (2015a) Cancer cell growth is differentially affected by constitutive activation of NRF2 by KEAP1 deletion and pharmacological activation of NRF2 by the synthetic triterpenoid, RTA 405. PLoS ONE 10:e0135257

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Probst BL, Trevino I, McCauley L, Bumeister R, Dulubova I, Wigley WC, Ferguson DA (2015b) RTA 408, A novel synthetic triterpenoid with broad anticancer and anti-inflammatory activity. PLoS One 10:e0122942

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Prochaska HJ, Santamaria AB (1988) Direct measurement of NAD(P)H:quinone reductase from cells cultured in microtiter wells: a screening assay for anticarcinogenic enzyme inducers. Anal Biochem 169:328–336

    Article  CAS  PubMed  Google Scholar 

  • Rachakonda G, Xiong Y, Sekhar KR, Stamer SL, Liebler DC, Freeman ML (2008) Covalent modification at Cys151 dissociates the electrophile sensor Keap1 from the ubiquitin ligase CUL3. Chem Res Toxicol 21:705–710

    Article  CAS  PubMed  Google Scholar 

  • Rajendran P, Nandakumar N, Rengarajan T, Palaniswami R, Gnanadhas EN, Lakshminarasaiah U, Gopas J, Nishigaki I (2014) Antioxidants and human diseases. Clin Chim Acta 436:332–347

    Article  CAS  PubMed  Google Scholar 

  • Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, Kensler TW, Yamamoto M, Petrache I, Tuder RM, Biswal S (2004) Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke–induced emphysema in mice. J Clin Investig 114:1248–1259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richardson BG, Jain AD, Potteti HR, Lazzara PR, David BP, Tamatam CR, Choma E, Skowron K, Dye K, Siddiqui Z, Wang Y-T, Krunic A, Reddy SP, Moore TW (2018) 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 61:8029–8047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robledinos-Anton N, Fernandez-Gines R, Manda G, Cuadrado A (2019) Activators and inhibitors of NRF2: a review of their potential for clinical development. Oxid Med Cell Longev 2019:9372182

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rushmore TH, Morton MR, Pickett CB (1991) The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem 266:11632–11639

    Article  CAS  PubMed  Google Scholar 

  • Saito T, Ichimura Y, Taguchi K, Suzuki T, Mizushima T, Takagi K, Hirose Y, Nagahashi M, Iso T, Fukutomi T, Ohishi M, Endo K, Uemura T, Nishito Y, Okuda S, Obata M, Kouno T, Imamura R, Tada Y, Obata R, Yasuda D, Takahashi K, Fujimura T, Pi J, Lee M-S, Ueno T, Ohe T, Mashino T, Wakai T, Kojima H, Okabe T, Nagano T, Motohashi H, Waguri S, Soga T, Yamamoto M, Tanaka K, Komatsu M (2016) p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming. Nat Commun 7:12030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schaap M, Hancock R, Wilderspin A, Wells G (2013) Development of a steady-state FRET-based assay to identify inhibitors of the Keap1-Nrf2 protein–protein interaction. Protein Sci 22:1812–1819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Selvin PR (2002) Principles and biophysical applications of lanthanide-based probes. Annu Rev Biophys Biomol Struct 31:275–302

    Article  CAS  PubMed  Google Scholar 

  • Sheng C, Dong G, Miao Z, Zhang W, Wang W (2015) State-of-the-art strategies for targeting protein–protein interactions by small-molecule inhibitors. Chem Soc Rev 44:8238–8259

    Article  CAS  PubMed  Google Scholar 

  • Simonian NA, Coyle JT (1996) Oxidative stress in neurodegenerative diseases. Annu Rev Pharm Toxicol 36:83–106

    Article  CAS  Google Scholar 

  • Sirota R, Gibson D, Kohen R (2015) The role of the catecholic and the electrophilic moieties of caffeic acid in Nrf2/Keap1 pathway activation in ovarian carcinoma cell lines. Redox Biol 4:48–59

    Article  CAS  PubMed  Google Scholar 

  • Sun H-P, Jiang Z-Y, Zhang M-Y, Lu M-C, Yang T-T, Pan Y, Huang H-Z, Zhang X-J, You Q-d (2014) Novel protein–protein interaction inhibitor of Nrf2–Keap1 discovered by structure-based virtual screening. MedChemComm 5:93–98

    Article  CAS  Google Scholar 

  • Suzuki T, Motohashi H, Yamamoto M (2013) Toward clinical application of the Keap1–Nrf2 pathway. Trends Pharm Sci 34:340–346

    Article  CAS  PubMed  Google Scholar 

  • Taguchi K, Maher JM, Suzuki T, Kawatani Y, Motohashi H, Yamamoto M (2010) Genetic analysis of cytoprotective functions supported by graded expression of Keap1. Mol Cell Biol 30:3016–3026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taguchi K, Motohashi H, Yamamoto M (2011) Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes Cells 16:123–140

    Article  CAS  PubMed  Google Scholar 

  • Tkachev V, Menshchikova E, Zenkov N (2011) Mechanism of the Nrf2/Keap1/ARE signaling system. Biochem (Mosc) 76:407–422

    Article  CAS  Google Scholar 

  • Tonelli C, Chio IIC, Tuveson DA (2017) Transcriptional regulation by Nrf2. Antioxid Redox Signal 29:1727–1745

    Article  PubMed  CAS  Google Scholar 

  • Tong KI, Katoh Y, Kusunoki H, Itoh K, Tanaka T, Yamamoto M (2006a) Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol Cell Biol 26:2887–2900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tong KI, Kobayashi A, Katsuoka F, Yamamoto M (2006b) Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. Biol Chem 387:1311–1320

    Article  CAS  PubMed  Google Scholar 

  • Tong KI, Padmanabhan B, Kobayashi A, Shang C, Hirotsu Y, Yokoyama S, Yamamoto M (2007) Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response. Mol Cell Biol 27:7511–7521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tran KT, Pallesen JS, Solbak SMØ, Narayanan D, Baig A, Zang J, Aguayo-Orozco A, Carmona RMC, Garcia AD, Bach A (2019) A comparative assessment study of known small-molecule Keap1−Nrf2 protein–protein interaction inhibitors: chemical synthesis, binding properties, and cellular activity. J Med Chem 62:802682

    Article  CAS  Google Scholar 

  • Vargas MR, Johnson DA, Sirkis DW, Messing A, Johnson JA (2008) Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J Neurosci 28:13574–13581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Walsh J, Jenkins RE, Wong M, Olayanju A, Powell H, Copple I, O’Neill PM, Goldring CEP, Kitteringham NR, Park BK (2014) Identification and quantification of the basal and inducible Nrf2-dependent proteomes in mouse liver: biochemical, pharmacological and toxicological implications. J Proteom 108:171–187

    Article  CAS  Google Scholar 

  • Wang H, Liu K, Geng M, Gao P, Wu X, Hai Y, Li Y, Li Y, Luo L, Hayes JD, Wang XJ, Tang X (2013) RXRα inhibits the NRF2-ARE signaling pathway through a direct interaction with the Neh7 domain of NRF2. Cancer Res 73:3097–3108

    Article  CAS  PubMed  Google Scholar 

  • Wen X, Thorne G, Hu L, Joy MS, Aleksunes LM (2015) Activation of NRF2 signaling in HEK293 cells by a first-in-class direct KEAP1-NRF2 inhibitor. J Biochem Mol Toxicol 29:261–266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Winkel AF, Engel CK, Margerie D, Kannt A, Szillat H, Glombik H, Kallus C, Ruf S, Güssregen S, Riedel J, Herling AW, von Knethen A, Weigert A, Brüne B, Schmoll D (2015) Characterization of RA839, a noncovalent small molecule binder to Keap1 and selective activator of Nrf2 signaling. J Biol Chem 290:28446–28455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woo SY, Kim JH, Moon MK, Han S-H, Yeon SK, Choi JW, Jang BK, Song HJ, Kang YG, Kim JW, Lee J, Kim DJ, Hwang O, Park KD (2014) Discovery of vinyl sulfones as a novel class of neuroprotective agents toward Parkinson’s disease therapy. J Med Chem 57:1473–1487

    Article  CAS  PubMed  Google Scholar 

  • Wruck CJ, Fragoulis A, Gurzynski A, Brandenburg L-O, Kan YW, Chan K, Hassenpflug J, Freitag-Wolf S, Varoga D, Lippross S, Pufe T (2011) Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice. Ann Rheum Dis 70:844–850

    Article  CAS  PubMed  Google Scholar 

  • Wu RP, Hayashi T, Cottam HB, Jin G, Yao S, Wu CCN, Rosenbach MD, Corr M, Schwab RB, Carson DA (2010) Nrf2 responses and the therapeutic selectivity of electrophilic compounds in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 107:7479–7484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamamoto T, Suzuki T, Kobayashi A, Wakabayashi J, Maher J, Motohashi H, Yamamoto M (2008) Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Mol Cell Biol 28:2758–2770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yasuda D, Nakajima M, Yuasa A, Obata R, Takahashi K, Ohe T, Ichimura Y, Komatsu M, Yamamoto M, Imamura R (2016) Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity. Bioorg Med Chem Lett 26:5956–5959

    Article  CAS  PubMed  Google Scholar 

  • Yasuda D, Yuasa A, Obata R, Nakajima M, Takahashi K, Ohe T, Ichimura Y, Komatsu M, Yamamoto M, Imamura R, Kojima H, Okabe T, Nagano T, Mashino T (2017) Discovery of benzo[g]indoles as a novel class of non-covalent Keap1-Nrf2 protein-protein interaction inhibitor. Bioorg Med Chem Lett 27:5006–5009

    Article  CAS  PubMed  Google Scholar 

  • Yoh K, Itoh K, Enomoto A, Hirayama A, Yamaguchi N, Kobayashi M, Morito N, Koyama A, Yamamoto M, Takahashi S (2001) Nrf2-deficient female mice develop lupus-like autoimmune nephritis. Kidney Int 60:1343–1353

    Article  CAS  PubMed  Google Scholar 

  • Yoshizaki Y, Mori T, Ishigami-Yuasa M, Kikuchi E, Takahashi D, Zeniya M, Nomura N, Mori Y, Araki Y, Ando F, Mandai S, Kasagi Y, Arai Y, Sasaki E, Yoshida S, Kagechika H, Rai T, Uchida S, Sohara E (2017) Drug-repositioning screening for Keap1-Nrf2 binding inhibitors using fluorescence correlation spectroscopy. Sci Rep. 7:3945

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • You Q-D, Jiang Z-Y, Lu M-C, Chen Z-Y, Sun H-P, Zhang X-J, Guo X-K, Xu X-L (2017) 1-Sulfonamido-4-aryloxy compound, and preparation method and medicinal application thereof. WO2017124835A1

  • Zhang DD, Hannink M (2003) 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 23:8137–8151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang DD, Lo S-C, Cross JV, Templeton DJ, Hannink M (2004) Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol 24:10941–10953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang DD, Lo S-C, Sun Z, Habib GM, Lieberman MW, Hannink M (2005) Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway. J Biol Chem 280:30091–30099

    Article  CAS  PubMed  Google Scholar 

  • Zhuang C, Narayanapillai S, Zhang W, Sham YY, Xing C (2014) Rapid identification of Keap1–Nrf2 small-molecule inhibitors through structure-based virtual screening and Hit-based substructure search. J Med Chem 57:1121–1126

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We gratefully acknowledge the financial support of grant CA133791 (to LH) from the National Institutes of Health.

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  1. Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA

    Sumi Lee & Longqin Hu

  2. Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA

    Longqin Hu

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Lee, S., Hu, L. Nrf2 activation through the inhibition of Keap1–Nrf2 protein–protein interaction. Med Chem Res 29, 846–867 (2020). https://doi.org/10.1007/s00044-020-02539-y

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