Characterization of RA839, a noncovalent small molecule binder to Keap1 and selective activator of Nrf2 signaling

Journal of Biological Chemistry

Volumn 290, Issue 47, 2015, Pages 28446-28455

  Winkel, Angelika F ^a   Engel, Christian K ^a   Margerie, Daniel ^a   Kannt, Aimo ^a,b   Szillat, Hauke ^a   Glombik, Heiner ^a   Kallus, Christopher ^a   Ruf, Sven ^a   Güssregen, Stefan ^a   Riedel, Jens ^a   Herling, Andreas W ^a   Von Knethen, Andreas ^c   Weigert, Andreas ^c   Brüne, Bernhard ^c   Schmoll, Dieter ^a  

^a SANOFI   (France)

^b UNIVERSITY OF HEIDELBERG   (Germany)

^c GOETHE UNIVERSITY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

BINS; CHEMICAL ACTIVATION; CHEMICAL COMPOUNDS; GENES; MACROPHAGES; MOLECULES; NITRIC OXIDE; PROBES; TRANSCRIPTION;

CELLULAR HOMEOSTASIS; CO-CRYSTALLIZATIONS; INDUCIBLE NITRIC OXIDE SYNTHASE; ISOTHERMAL TITRATION CALORIMETRY; LIPOPOLYSACCHARIDES; NITRIC OXIDE RELEASE; SELECTIVE INHIBITORS; TARGET GENE EXPRESSION;

GENE EXPRESSION;

1 [4 [(2,3,5,6 TETRAMETHYLPHENYL)SULFOSULFONYLAMINO] 1 NAPHTHYL]PYRROLIDINE 3 CARBOXYLIC ACID; BARDOXOLONE METHYL; GENOMIC DNA; INDUCIBLE NITRIC OXIDE SYNTHASE; KELCH LIKE ECH ASSOCIATED PROTEIN 1; LIPOPOLYSACCHARIDE; NITRIC OXIDE; PROTEIN INHIBITOR; TRANSCRIPTION FACTOR NRF2; UNCLASSIFIED DRUG; KEAP1 PROTEIN, HUMAN; NFE2L2 PROTEIN, HUMAN; PROTEIN BINDING; PYRROLIDINE DERIVATIVE; RA839 COMPOUND; SIGNAL PEPTIDE; SULFONAMIDE;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; BONE MARROW; CHEMICAL BOND; CONTROLLED STUDY; CRYSTALLIZATION; DNA MICROARRAY; DRUG PROTEIN BINDING; DRUG STRUCTURE; GENE EXPRESSION REGULATION; GENE SILENCING; GENE TARGETING; ISOTHERMAL TITRATION CALORIMETRY; MACROPHAGE; MALE; MOUSE; NONCOVALENT BINDING; NONHUMAN; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN INDUCTION; PROTEIN PROTEIN INTERACTION; REAL TIME POLYMERASE CHAIN REACTION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SIGNAL TRANSDUCTION; X RAY CRYSTALLOGRAPHY; ANIMAL; DRUG EFFECTS; METABOLISM;

ANIMALS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; KELCH-LIKE ECH-ASSOCIATED PROTEIN 1; MALE; MICE; NF-E2-RELATED FACTOR 2; PROTEIN BINDING; PYRROLIDINES; SIGNAL TRANSDUCTION; SULFONAMIDES;

EID: 84947738398     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M115.678136     Document Type: Article

References (40)

1. Hayes, J. D., and Dinkova-Kostova, A. T. (2014) The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem. Sci. 39, 199-218
2. Suzuki, T., Motohashi, H., and Yamamoto, M. (2013) Toward clinical application of the Keap1-Nrf2 pathway. Trends Pharmacol. Sci. 34, 340-346
3. Niture, S. K., Khatri, R., and Jaiswal, A. K. (2014) Regulation of Nrf2-an update. Free Radic. Biol. Med. 66, 36-44
4. Gao, B., Doan, A., and Hybertson, B. M. (2014) The clinical potential of influencing Nrf2 signaling in degenerative and immunological disorders. Clin. Pharmacol. 6, 19-34
5. Kwak, M. K., and Kensler, T. W. (2010) Targeting NRF2 signaling for cancer chemoprevention. Toxicol. Appl. Pharmacol. 244, 66-76
6. Tong, K. I., Kobayashi, A., Katsuoka, F., and Yamamoto, M. (2006) Twosite substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. Biol. Chem. 387, 1311-1320
7. Tong, K. I., Padmanabhan, B., Kobayashi, A., Shang, C., Hirotsu, Y., Yokoyama, S., and 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
8. Baird, L., Swift, S., Llères, D., and Dinkova-Kostova, A. T. (2014) Monitoring Keap1-Nrf2 interactions in single live cells. Biotechnol. Adv. 32, 1133-1144
9. Liby, K. T., and Sporn, M. B. (2012) Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol. Rev. 64, 972-1003
10. Scannevin, R. H., Chollate, S., Jung, M. Y., Shackett, M., Patel, H., Bista, P., Zeng, W., Ryan, S., Yamamoto, M., Lukashev, M., and Rhodes, K. J. (2012) Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J. Pharmacol. Exp. Ther. 341, 274-284
11. Cleasby, A., Yon, J., Day, P. J., Richardson, C., Tickle, I. J., Williams, P. A., Callahan, J. F., Carr, R., Concha, N., Kerns, J. K., Qi, H., Sweitzer, T., Ward, P., and Davies, T. G. (2014) Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO. PLoS One 9, e98896
12. Tran, Q. T., Xu, L., Phan, V., Goodwin, S. B., Rahman, M., Jin, V. X., Sutter, C. H., Roebuck, B. D., Kensler, T. W., George, E. O., and Sutter, T. R. (2009) Chemical genomics of cancer chemopreventive dithiolethiones. Carcinogenesis 30, 480-486
13. Yates, M. S., and Kensler, T. W. (2007) Keap1 eye on the target: chemoprevention of liver cancer. Acta Pharmacol. Sin. 28, 1331-1342
14. Takaya, K., Suzuki, T., Motohashi, H., Onodera, K., Satomi, S., Kensler, T. W., and Yamamoto, M. (2012) Validation of the multiple sensor mechanism of the Keap1-Nrf2 system. Free Radic. Biol. Med. 53, 817-827
15. Pergola, P. E., Raskin, P., Toto, R. D., Meyer, C. J., Huff, J. W., Grossman, E. B., Krauth, M., Ruiz, S., Audhya, P., Christ-Schmidt, H., Wittes, J., Warnock, D. G., and BEAM Study Investigators (2011) Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N. Engl. J. Med. 365, 327-336
16. Gold, R., Kappos, L., Arnold, D. L., Bar-Or, A., Giovannoni, G., Selmaj, K., Tornatore, C., Sweetser, M. T., Yang, M., Sheikh, S. I., Dawson, K. T., and DEFINE Study Investigators (2012) Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N. Engl. J. Med. 367, 1098-1107
17. de Zeeuw, D., Akizawa, T., Audhya, P., Bakris, G. L., Chin, M., Christ- Schmidt, H., Goldsberry, A., Houser, M., Krauth, M., Lambers Heerspink, H. J., McMurray, J. J., Meyer, C. J., Parving, H. H., Remuzzi, G., Toto, R. D., Vaziri, N. D., Wanner, C., Wittes, J., Wrolstad, D., Chertow, G. M., and BEACON Trial Investigators (2013) Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N. Engl. J. Med. 369, 2492-2503
18. Chen, H., Assmann, J. C., Krenz, A., Rahman, M., Grimm, M., Karsten, C. M., Köhl, J., Offermanns, S., Wettschureck, N., and Schwaninger, M. (2014) Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate's protective effect in EAE. J. Clin. Invest. 124, 2188-2192
19. Park, B. K., Boobis, A., Clarke, S., Goldring, C. E., Jones, D., Kenna, J. G., Lambert, C., Laverty, H. G., Naisbitt, D. J., Nelson, S., Nicoll-Griffith, D. A., Obach, R. S., Routledge, P., Smith, D. A., Tweedie, D. J., Vermeulen, N., Williams, D. P., Wilson, I. D., and Baillie, T. A. (2011) Managing the challenge of chemically reactive metabolites in drug development. Nat. Rev. Drug Discov. 10, 292-306
20. Jiang, Z. Y., Lu, M. C., Xu, L. L., Yang, T. T., Xi, M. Y., Xu, X. L., Guo, X. K., Zhang, X. J., You, Q. D., and Sun, H. P. (2014) Discovery of potent Keap1- Nrf2 protein-protein interaction inhibitor based on molecular binding determinants analysis. J. Med. Chem. 57, 2736-2745
21. Hu, L., Magesh, S., Chen, L., Wang, L., Lewis, T. A., Chen, Y., Khodier, C., Inoyama, D., Beamer, L. J., Emge, T. J., Shen, J., Kerrigan, J. E., Kong, A. N., Dandapani, S., Palmer, M., Schreiber, S. L., and Munoz, B. (2013) Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein- protein interaction. Bioorg. Med. Chem. Lett. 23, 3039-3043
22. 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., and 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
23. Richter, M., Winkel, A. F., Schummer, D., Gerlitz, M., de Hoop, M., Brunner, B., Glien, M., and Schmoll, D. (2014) Pau d'arco activates Nrf2-dependent gene expression via the MEK/ERK-pathway. J. Toxicol. Sci. 39, 353-361
24. Kuchler, L., Giegerich, A. K., Sha, L. K., Knape, T., Wong, M. S., Schröder, K., Brandes, R. P., Heide, H., Wittig, I., Brüne, B., and von Knethen, A. (2014) SYNCRIP-dependent Nox2 mRNA destabilization impairs ROS formation in M2-polarized macrophages. Antioxid. Redox Signal. 21, 2483-2497
25. Halland, N., Brönstrup, M., Czech, J., Czechtizky, W., Evers, A., Follmann, M., Kohlmann, M., Schiell, M., Kurz, M., Schreuder, H. A., and Kallus, C. (2015) Novel small molecule inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa) from natural product anabaenopeptin. J. Med. Chem. 58, 4839-4844
26. Anderka, O., Boyken, J., Aschenbach, U., Batzer, A., Boscheinen, O., and Schmoll, D. (2008) Biophysical characterization of the interaction between hepatic glucokinase and its regulatory protein: impact of physiological and pharmacological effectors. J. Biol. Chem. 283, 31333-31340
27. Honda, T., Rounds, B. V., Bore, L., Finlay, H. J., Favaloro, F. G., Jr., Suh, N., Wang, Y., Sporn, M. B., and Gribble, G. W. (2000) 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. 43, 4233-4246
28. Tong, K. I., Katoh, Y., Kusunoki, H., Itoh, K., Tanaka, T., and Yamamoto, M. (2006) Keap1 recruits Neh2 through binding to ETGE andDLGmotifs: characterization of the two-site molecular recognition model. Mol. Cell. Biol. 26, 2887-2900
29. Haxaire, C., Turpin, F. R., Potier, B., Kervern, M., Sinet, P. M., Barbanel, G., Mothet, J. P., Dutar, P., and Billard, J. M. (2012) Reversal of age-related oxidative stress prevents hippocampal synaptic plasticity deficits by protecting D-serine-dependent NMDA receptor activation. Aging Cell 11, 336-344
30. Qiu, S. L., Xiao, Z. C., Piao, C. M., Xian, Y. L., Jia, L. X., Qi, Y. F., Han, J. H., Zhang, Y. Y., and Du, J. (2014) AMP-activated protein kinase α2 protects against liver injury from metastasized tumors via reduced glucose deprivation- induced oxidative stress. J. Biol. Chem. 289, 9449-9459
31. Zong, J., Deng, W., Zhou, H., Bian, Z. Y., Dai, J., Yuan, Y., Zhang, J. Y., Zhang, R., Zhang, Y., Wu, Q. Q., Guo, H. P., Li, H. L., and Tang, Q. Z. (2013) 3,3'-Diindolylmethane protects against cardiac hypertrophy via 5'-adenosine monophosphate-activated protein kinase-alpha2. PLoS One 8, e53427
32. Gjyshi, O., Bottero, V., Veettil, M. V., Dutta, S., Singh, V. V., Chikoti, L., and Chandran, B. (2014) Kaposi's sarcoma-associated herpesvirus induces Nrf2 during de novo infection of endothelial cells to create a microenvi-ronment conducive to infection. PLoS Pathog. 10, e1004460
33. Kim, S. W., Lee, H. K., Shin, J. H., and Lee, J. K. (2013) Up-down regulation of HO-1 and iNOS gene expressions by ethyl pyruvate via recruiting p300 to Nrf2 and depriving it from p65. Free Radic. Biol. Med. 65, 468-476
34. Komatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y., Sou, Y. S., Ueno, I., Sakamoto, A., Tong, K. I., Kim, M., Nishito, Y., Iemura, S., Natsume, T., Ueno, T., Kominami, E., Motohashi, H., Tanaka, K., and Yamamoto, M. (2010) The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell Biol. 12, 213-223
35. Hall, E. T., and Bhalla, V. (2014) Is there a sweet spot for Nrf2 activation in the treatment of diabetic kidney disease? Diabetes 63, 2904-2905
36. Zhang, D. D. (2013) Bardoxolone brings Nrf2-based therapies to light. Antioxid. Redox Signal. 19, 517-518
37. To, C., Shilton, B. H., and Di Guglielmo, G. M. (2010) Synthetic triterpenoids target the Arp2/3 complex and inhibit branched actin polymerization. J. Biol. Chem. 285, 27944-27957
38. Zoja, C., Benigni, A., and Remuzzi, G. (2014) The Nrf2 pathway in the progression of renal disease. Nephrol. Dial. Transplant 29, i19-i24
39. Harris, R. C. (2013) The best-laid plans. Am. J. Physiol. Renal Physiol. 304, F1086-F1087
40. Weerachayaphorn, J., Luo, Y., Mennone, A., Soroka, C. J., Harry, K., and Boyer, J. L. (2014) Deleterious effect of oltipraz on extrahepatic cholestasis in bile duct-ligated mice. J. Hepatol. 60, 160-166