Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents

Acta Pharmaceutica Sinica B

Volumn 5, Issue 4, 2015, Pages 285-299

  Abed, Dhulfiqar Ali ^a   Goldstein, Melanie ^a   Albanyan, Haifa ^a   Jin, Huijuan ^a   Hu, Longqin ^a,b  

^a RUTGERS UNIVERSITY   (United States)

^b SHANXI MEDICAL UNIVERSITY   (China)

Author keywords

Direct inhibitors of protein protein interaction; High throughput screening assays; Keap1; Nrf2; Oxidative stress; Structure activity relationships; X ray crystallography

Indexed keywords

10MER NRF2 PEPTIDE; 11MER NRF2 PEPTIDE; 12MER NRF2 PEPTIDE; 14MER NRF2 PEPTIDE; 16MER NRF2 PEPTIDE; 7MER NRF2 PEPTIDE; 8MER NRF2 AMIDE PEPTIDE; 8MER NRF2 PEPTIDE; 9MER NRF2 AMIDE PEPTIDE; 9MER NRF2 PEPTIDE; AC 9MER NRF2 AMIDE PEPTIDE; AC 9MER NRF2 PEPTIDE; KELCH LIKE ECH ASSOCIATED PROTEIN 1; LH 601A; LH 601B; LH 601C; LH 601D; PROTEIN INHIBITOR; REACTIVE OXYGEN METABOLITE; TRANSCRIPTION FACTOR NRF2; UNCLASSIFIED DRUG;

ANTIOXIDANT RESPONSIVE ELEMENT; BINDING AFFINITY; CARDIOVASCULAR DISEASE; CELL BASED NEH2 LUCIFERASE ASSAY; CHRONIC OBSTRUCTIVE LUNG DISEASE; CRYSTAL STRUCTURE; DEGENERATIVE DISEASE; DIABETES MELLITUS; DIABETIC CARDIOMYOPATHY; DIABETIC NEUROPATHY; DRUG SCREENING; ELECTROPHILICITY; FLUORESCENCE POLARIZATION; GASTROINTESTINAL DISEASE; HIGH THROUGHPUT SCREENING; HUMAN; INHIBITION KINETICS; NEOPLASM; NONHUMAN; OXIDATIVE STRESS; PATHOGENESIS; PROTEIN ANALYSIS; PROTEIN BINDING; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; PROTEIN TARGETING; REGULATORY MECHANISM; RESPIRATORY TRACT DISEASE; REVIEW; SIGNAL TRANSDUCTION; STRUCTURE ACTIVITY RELATION; SURFACE PLASMON RESONANCE;

EID: 84947201524     PISSN: 22113835     EISSN: 22113843     Source Type: Journal    
DOI: 10.1016/j.apsb.2015.05.008     Document Type: Review

References (117)

1. De Bont R, van Larebeke N. Endogenous DNA damage in humans: a review of quantitative data. Mutagenesis 2004, 19:169-185.
2. Sedelnikova OA, Redon CE, Dickey JS, Nakamura AJ, Georgakilas AG, Bonner WM. Role of oxidatively induced DNA lesions in human pathogenesis. Mutat Res 2010, 704:152-159.
3. Li J, Wuliji O, Li W, Jiang ZG, Ghanbari HA. Oxidative stress and neurodegenerative disorders. Int J Mol Sci 2013, 14:24438-24475.
4. Dinkova-Kostova AT, Talalay P. Direct and indirect antioxidant properties of inducers of cytoprotective proteins. Mol Nutr Food Res 2008, 52 Suppl 1:S128-S138.
5. Lakowicz JR. Principles of fluorescence spectroscopy 2006, Springer Science and Business Media, New York. 3rd ed.
6. Lyakhovich VV, Vavilin VA, Zenkov NK, Menshchikova EB. Active defense under oxidative stress. The antioxidant responsive element. Biochemistry 2006, 71:962-974.
7. Magesh S, Chen Y, Hu LQ. Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents. Med Res Rev 2012, 32:687-726.
8. Lee JM, Johnson JA. An important role of Nrf2-ARE pathway in the cellular defense mechanism. J Biochem Mol Biol 2004, 37:139-143.
9. Nioi P, McMahon M, Itoh K, Yamamoto M, Hayes JD. 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 2003, 374:337-348.
10. Rushmore TH, Morton MR, Pickett CB. The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem 1991, 266:11632-11639.
11. Wakabayashi N, Slocum SL, Skoko JJ, Shin S, Kensler TW. When Nrf2 talks, who[U+05F3]s listening?. Antioxid Redox Signal 2010, 13:1649-1663.
12. Katsuoka F, Motohashi H, Ishii T, Aburatani H, Engel JD, Yamamoto M. Genetic evidence that small maf proteins are essential for the activation of antioxidant response element-dependent genes. Mol Cell Biol 2005, 25:8044-8051.
13. McMahon M, Itoh K, Yamamoto M, Chanas SA, Henderson CJ, McLellan LI, et al. The cap [U+05F3]n[U+05F3] collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Res 2001, 61:3299-3307.
14. Li Y, Paonessa JD, Zhang Y. Mechanism of chemical activation of Nrf2. PLoS One 2012, 7:e35122.
15. Moi P, Chan K, Asunis I, Cao A, Kan YW. 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 β-globin locus control region. Proc Natl Acad Sci U S A 1994, 91:9926-9930.
16. Itoh K, Mimura J, Yamamoto M. Discovery of the Negative Regulator of Nrf2, Keap1: a historical overview. Antioxid Redox Signal 2010, 13:1665-1678.
17. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, 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.
18. Jain AK, Bloom DA, Jaiswal AK. Nuclear import and export signals in control of Nrf2. J Biol Chem 2005, 280:29158-29168.
19. Jung KA, Kwak MK. The Nrf2 system as a potential target for the development of indirect antioxidants. Molecules 2010, 15:7266-7291.
20. Katoh Y, Iida K, Kang MI, Kobayashi A, Mizukami M, Tong KI, et al. Evolutionary conserved N-terminal domain of Nrf2 is essential for the Keap1-mediated degradation of the protein by proteasome. Arch Biochem Biophys 2005, 433:342-350.
21. Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol 2004, 24:10941-10953.
22. Katoh Y, Itoh K, Yoshida E, Miyagishi M, Fukamizu A, Yamamoto M. Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells 2001, 6:857-868.
23. McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD. 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.
24. Tkachev VO, Menshchikova EB, Zenkov NK. Mechanism of the Nrf2/Keap1/ARE signaling system. Biochemistry 2011, 76:407-422.
25. Itoh K, Tong KI, Yamamoto M. Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles. Free Radic Biol Med 2004, 36:1208-1213.
26. Zipper LM, Mulcahy RT The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm. J Biol Chem 2002, 277:36544-36552.
27. Chauhan N, Chaunsali L, Deshmukh P, Padmanabhan B. Analysis of dimerization of BTB-IVR domains of Keap1 and its interaction with Cul3, by molecular modeling. Bioinformation 2013, 9:450-455.
28. Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, 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 U S A 2002, 99:11908-11913.
29. 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.
30. Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, et al. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol 2004, 24:7130-7139.
31. Li XC, Zhang DN, Hannink M, Beamer LJ. Crystal structure of the kelch domain of human Keap1. J Biol Chem 2004, 279:54750-54758.
32. Uruno A, Motohashi H. The Keap1-Nrf2 system as an in vivo sensor for electrophiles. Nitric Oxide 2011, 25:153-160.
33. Stepkowski TM, Kruszewski MK. Molecular cross-talk between the NRF2/KEAP1 signaling pathway, autophagy, and apoptosis. Free Radic Biol Med 2011, 50:1186-1195.
34. Kobayashi A, Kang MI, Watai Y, Tong KI, Shibata T, Uchida K, et al. Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol Cell Biol 2006, 26:221-229.
35. Zhang DD, Lo SC, Sun Z, Habib GM, Lieberman MW, Hannink M. Ubiquitination of Keap1, a BTB-kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway. J Biol Chem 2005, 280:30091-30099.
36. McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD. 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 2006, 281:24756-24768.
37. Baird L, Dinkova-Kostova AT. The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol 2011, 85:241-272.
38. Suzuki T, Motohashi H, Yamamoto M. Toward clinical application of the Keap1-Nrf2 pathway. Trends Pharmacol Sci 2013, 34:340-346.
39. Eggler AL, Small E, Hannink M, Mesecar AD. Cul3-mediated Nrf2 ubiquitination and antioxidant response element (ARE) activation are dependent on the partial molar volume at position 151 of Keap1. Biochem J 2009, 422:171-180.
40. Tong KI, Katoh Y, Kusunoki H, Itoh K, Tanaka T, Yamamoto M. 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.
41. Rachakonda G, Xiong Y, Sekhar KR, Stamer SL, Liebler DC, Freeman ML. Covalent modification at Cys151 dissociates the electrophile sensor Keap1 from the ubiquitin ligase CUL3. Chem Res Toxicol 2008, 21:705-710.
42. He XQ, Ma Q. NRF2 cysteine residues are critical for oxidant/electrophile-sensing, kelch-like ECH-associated protein-1-dependent ubiquitination-proteasomal degradation, and transcription activation. Mol Pharmacol 2009, 76:1265-1278.
43. Yamamoto T, Suzuki T, Kobayashi A, Wakabayashi J, Maher J, Motohashi H, et al. Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Mol Cell Biol 2008, 28:2758-2770.
44. Sun Z, Zhang S, Chan JY, Zhang DD. Keap1 controls postinduction repression of the Nrf2-mediated antioxidant response by escorting nuclear export of Nrf2. Mol Cell Biol 2007, 27:6334-6349.
45. Kobayashi M, Li L, Iwamoto N, Nakajima-Takagi Y, Kaneko H, Nakayama Y, et al. The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds. Mol Cell Biol 2009, 29:493-502.
46. Tong KI, Kobayashi A, Katsuoka F, Yamamoto M. Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. Biol Chem 2006, 387:1311-1320.
47. Tong KI, Padmanabhan B, Kobayashi A, Shang CW, Hirotsu Y, Yokoyama S, 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.
48. Motohashi H, Yamamoto M. Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med 2004, 10:549-557.
49. Rajendran P, Nandakumar N, Rengarajan T, Palaniswami R, Gnanadhas EN, Lakshminarasaiah U, et al. Antioxidants and human diseases. Clin Chim Acta 2014, 436:332-347.
50. Lewis KN, Mele J, Hayes JD, Buffenstein R. Nrf2 a guardian of healthspan and gatekeeper of species longevity. Integr Comp Biol 2010, 50:829-843.
51. Kansanen E, Kuosmanen SM, Leinonen H, Levonen A.. The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Redox Biol 2013, 1:45-49.
52. Hayes JD, McMahon M. NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci 2009, 34:176-188.
53. Kensler TW, Wakabayashi N. Nrf2: friend or foe for chemoprevention?. Carcinogenesis 2010, 31:90-99.
54. Xiang MJ, Namani A, Wu SJ, Wang XL. Nrf2: bane or blessing in cancer?. J Cancer Res Clin Oncol 2014, 140:1251-1259.
55. Gañán-Gómez I, Wei Y, Yang H, Boyano-Adánez MC, García-Manero G. Oncogenic functions of the transcription factor Nrf2. Free Radic Biol Med 2013, 65:750-764.
56. Ren DM, Villeneuve NF, Jiang T, Wu TD, Lau A, Toppin HA, et al. Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci U S A 2011, 108:1433-1438.
57. Chian S, Thapa R, Chi ZX, Wang XJ, Tang XW. Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo. Biochem Biophys Res Commun 2014, 447:602-608.
58. De Vries HE, Witte M, Hondius D, Rozemuller AJM, Drukarch B, Hoozemans J, et al. Nrf2-induced antioxidant protection: a promising target to counteract ROS-mediated damage in neurodegenerative disease?. Free Radic Biol Med 2008, 45:1375-1383.
59. Sandberg M, Patil J, D[U+05F3]Angelo B, Weber SG, Mallard C. NRF2-regulation in brain health and disease: implication of cerebral inflammation. Neuropharmacology 2014, 79:298-306.
60. Zhang MJ, An CR, Gao YQ, Leak RK, Chen J, Zhang F. Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection. Prog Neurobiol 2013, 100:30-47.
61. Gan L, Johnson JA. Oxidative damage and the Nrf2-ARE pathway in neurodegenerative diseases. Biochim Biophys Acta 2014, 1842:1208-1218.
62. Yoh K, Hirayama A, Ishizaki K, Yamada A, Takeuchi M, Yamagishi S, et al. Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2-deficient mice. Genes Cells 2008, 13:1159-1170.
63. Pi JB, Zhang Q, Fu JQ, Woods CG, Hou YY, Corkey BE, et al. ROS signaling, oxidative stress and Nrf2 in pancreatic beta-cell function. Toxicol Appl Pharmacol 2010, 244:77-83.
64. Bai Y, Cui WP, Xin Y, Miao X, Barati MT, Zhang C, et al. Prevention by sulforaphane of diabetic cardiomyopathy is associated with up-regulation of Nrf2 expression and transcription activation. J Mol Cell Cardiol 2013, 57:82-95.
65. Jiménez-Osorio AS, Picazo A, González-Reyes S, Barrera-Oviedo D, Rodríguez-Arellano ME, Pedraza-Chaverri J. Nrf2 and redox status in prediabetic and diabetic patients. Int J Mol Sci 2014, 15:20290-20305.
66. Velmurugan GV, Sundaresan NR, Gupta MP, White C. Defective Nrf2-dependent redox signalling contributes to microvascular dysfunction in type 2 diabetes. Cardiovasc Res 2013, 100:143-150.
67. Uruno A, Yagishita Y, Yamamoto M. The Keap1-Nrf2 system and diabetes mellitus. Arch Biochem Biophys 2014, 566:76-84.
68. Bhakkiyalakshmi E, Sireesh D, Rajaguru P, Paulmurugan R, Ramkumar KM. The emerging role of redox-sensitive Nrf2-Keap1 pathway in diabetes. Pharmacol Res 2015, 91:104-114.
69. Jiang T, Huang ZP, Lin YF, Zhang ZG, Fang DY, Zhang DD. The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy. Diabetes 2010, 59:850-860.
70. Choi BH, Kang KS, Kwak MK. Effect of redox modulating NRF2 activators on chronic kidney disease. Molecules 2014, 19:12727-12759.
71. Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. New Engl J Med 2011, 365:327-336.
72. Boutten A, Goven D, Artaud-Macari E, Boczkowski J, Bonay M. NRF2 targeting: a promising therapeutic strategy in chronic obstructive pulmonary disease. Trends Mol Med 2011, 17:363-371.
73. Cho HY, Kleeberger SR. Nrf2 protects against airway disorders. Toxicol Appl Pharmacol 2010, 244:43-56.
74. Reddy SP. The antioxidant response element and oxidative stress modifiers in airway diseases. Curr Mol Med 2008, 8:376-383.
75. Hübner RH, Schwartz JD, De Bishnu P, Ferris B, Omberg L, Mezey JG, et al. Coordinate control of expression of Nrf2-modulated genes in the human small airway epithelium is highly responsive to cigarette smoking. Mol Med 2009, 15:203-219.
76. Rangasamy T, Cho CY, Thimmulappa RK, Zhen LJ, Srisuma SS, Kensler TW, et al. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Investig 2004, 114:1248-1259.
77. Biswal S, Thimmulappa RK, Harvey CJ. Experimental therapeutics of Nrf2 as a target for prevention of bacterial exacerbations in COPD. Proc Am Thorac Soc 2012, 9:47-51.
78. Li J, Ichikawa T, Janicki JS, Cui T. Targeting the Nrf2 pathway against cardiovascular disease. Expert Opin Ther Targets 2009, 13:785-794.
79. Dreger H, Westphal K, Wilck N, Baumann G, Stangl V, Stangl K, et al. Protection of vascular cells from oxidative stress by proteasome inhibition depends on Nrf2. Cardiovasc Res 2010, 85:395-403.
80. Collins AR, Lyon CJ, Xia X, Liu JZ, Tangirala RK, Yin F, et al. Age-accelerated atherosclerosis correlates with failure to upregulate antioxidant genes. Circ Res 2009, 104:e42-e54.
81. Ruotsalainen A., Inkala M, Partanen ME, Lappalainen JP, Kansanen E, Mäkinen PI, et al. The absence of macrophage Nrf2 promotes early atherogenesis. Cardiovasc Res 2013, 98:107-115.
82. Khor TO, Huang MT, Kwon KH, Chan JY, Reddy BS, Kong AN. Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res 2006, 66:11580-11584.
83. Jena G, Trivedi PP, Sandala B. Oxidative stress in ulcerative colitis: an old concept but a new concern. Free Radic Res 2012, 46:1339-1345.
84. Stachel I, Geismann C, Aden K, Deisinger F, Rosenstiel P, Schreiber S, et al. Modulation of nuclear factor E2-related factor 2 (Nrf2) activation by the stress response gene immediate early response-3 (IER3) in colonic epithelial cells: a novel mechanism of cellular adaption to inflammatory stress. J Biol Chem 2014, 289:1917-1929.
85. Aleksunes LM, Manautou JE. Emerging role of Nrf2 in protecting against hepatic and gastrointestinal disease. Toxicol Pathol 2007, 35:459-473.
86. Okawa H, Motohashi H, Kobayashi A, Aburatani H, Kensler TW, Yamamoto M. Hepatocyte-specific deletion of the Keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. Biochem Biophys Res Commun 2006, 339:79-88.
87. Qu Q, Liu J, Zhou HH, Klaassen CD. Nrf2 protects against furosemide-induced hepatotoxicity. Toxicology 2014, 324:35-42.
88. García-Niño WR, Pedraza-Chaverrí J. Protective effect of curcumin against heavy metals-induced liver damage. Food Chem Toxicol 2014, 69:182-201.
89. Klaassen CD, Reisman SA. Nrf2 the rescue: effects of the antioxidative/electrophilic response on the liver. Toxicol Appl Pharmacol 2010, 244:57-65.
90. Kurzawski M, Dziedziejko V, Urasińska E, Post M, Wójcicki M, Mietkiewski J, et al. Nuclear factor erythroid 2-like 2 (Nrf2) expression in end-stage liver disease. Environ Toxicol Pharmacol 2012, 34:87-95.
91. Deramaudt TB, Dill C, Bonay M. Regulation of oxidative stress by Nrf2 in the pathophysiology of infectious diseases. Méd Mal Infect 2013, 43:100-107.
92. Schaedler S, Krause J, Himmelsbach K, Carvajal-Yepes M, Lieder F, Klingel K, et al. Hepatitis B virus induces expression of antioxidant response element-regulated genes by activation of Nrf2. J Biol Chem 2010, 285:41074-41086.
93. Thimmulappa RK, Lee H, Rangasamy T, Reddy SP, Yamamoto M, Kensler TW, et al. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Investig 2006, 116:984-995.
94. Maicas N, Ferrándiz ML, Brines R, Ibáñez L, Cuadrado A, Koenders MI, et al. Deficiency of Nrf2 accelerates the effector phase of arthritis and aggravates joint disease. Antioxid Redox Signal 2011, 15:889-901.
95. Wruck CJ, Fragoulis A, Gurzynski A, Brandenburg LO, Kan YW, Chan KM, et al. Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice. Ann Rheum Dis 2011, 70:844-850.
96. Córdova EJ, Velázquez-Cruz R, Centeno F, Baca V, Orozco L. The NRF2 gene variant, -653G/A, is associated with nephritis in childhood-onset systemic lupus erythematosus. Lupus 2010, 19:1237-1242.
97. Braun S, Hanselmann C, Gassmann MG, Auf Dem Keller U, Born-Berclaz C, Chan KM, et al. Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound. Mol Cell Biol 2002, 22:5492-5505.
98. Beyer TA, Auf Dem Keller U, Braun S, Schäfer M, Werner S. Roles and mechanisms of action of the Nrf2 transcription factor in skin morphogenesis, wound repair and skin cancer. Cell Death Differ 2007, 14:1250-1254.
99. Nagai N, Thimmulappa RK, Cano M, Fujihara M, Izumi-Nagai K, Kong XN, et al. Nrf2 is a critical modulator of the innate immune response in a model of uveitis. Free Radic Biol Med 2009, 47:300-306.
100. Eggler AL, Gay KA, Mesecar AD. Molecular mechanisms of natural products in chemoprevention: induction of cytoprotective enzymes by Nrf2. Mol Nutr Food Res 2008, 52 Suppl 1:S84-S94.
101. Hur W, Gray NS. Small molecule modulators of antioxidant response pathway. Curr Opin Chem Biol 2011, 15:162-173.
102. Hu LQ, Magesh S, Chen L, Wang LL, Lewis TA, Chen Y, et al. Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction. Bioorg Med Chem Lett 2013, 23:3039-3043.
103. Jiang ZY, Lu MC, Xu LL, Yang TT, Xi MY, Xu XL, et al. Discovery of potent Keap1-Nrf2 protein-protein interaction inhibitor based on molecular binding determinants analysis. J Med Chem 2014, 57:2736-2745.
104. Chen Y, Inoyama D, Kong A., Beamer LJ, Hu L. 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 2011, 78:1014-1021.
105. Huang XY. Fluorescence polarization competition assay: the range of resolvable inhibitor potency is limited by the affinity of the fluorescent ligand. J Biomol Screen 2003, 8:34-38.
106. Inoyama D, Chen Y, Huang XY, Beamer LJ, Kong A., Hu L. 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.
107. Smirnova NA, Haskew-Layton RE, Basso M, Hushpulian DM, Payappilly JB, Speer RE, et al. Development of Neh2-luciferase reporter and its application for high throughput screening and real-time monitoring of Nrf2 activators. Chem Biol 2011, 18:752-765.
108. Lo SC, Li XC, Henzl MT, Beamer LJ, Hannink M. Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling. EMBO J 2006, 25:3605-3617.
109. Hancock R, Bertrand HC, Tsujita T, Naz S, El-Bakry A, Laoruchupong J, et al. Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction. Free Radic Biol Med 2012, 52:444-451.
110. Hancock R, Schaap M, Pfister H, Wells G. Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction with improved binding and cellular activity. Org Biomol Chem 2013, 11:3553-3557.
111. Steel R, Cowan J, Payerne E, O'Connell MA, Searcey M. Anti-inflammatory effect of a cell-penetrating peptide targeting the Nrf2/Keap1 interaction. ACS Med Chem Lett 2012, 3:407-410.
112. Sun HP, Jiang ZY, Zhang MY, Lu MC, Yang TT, Pan Y, et al. Novel protein-protein interaction inhibitor of Nrf2-Keap1 discovered by structure-based virtual screening. Med Chem Commun 2014, 5:93-98.
113. Jnoff E, Albrecht C, Barker JJ, Barker O, Beaumont E, Bromidge S, et al. Binding mode and structure-activity relationships around direct inhibitors of the Nrf2-Keap1 complex. ChemMedChem 2014, 9:699-705.
114. Marcotte D, Zeng WK, Hus J., McKenzie A, Hession C, Jin P, et al. Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism. Bioorg Med Chem 2013, 21:4011-4019.
115. Zhuang CL, Narayanapillai S, Zhang WN, Sham YY, Xing CG. Rapid identification of Keap1-Nrf2 small-molecule inhibitors through structure-based virtual screening and hit-based substructure search. J Med Chem 2014, 57:1121-1126.
116. Sato M, Aoki T, Inoue H, Tanaka T, Kunishima N, inventors. Keap1 protein binding compound, crystal of complex between the same and Keap1 protein, and method for producing the same. Toray Ind Inc., assignee. Japanese Patent JP 2013-028575A. 2013 February 7.
117. Beamer LJ, Li X, Bottoms CA, Hannink M. Conserved solvent and side-chain interactions in the 1.35 angstrom structure of the Kelch domain of Keap1. Biol Crystallogr 2005, 61:1335-1342.