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Nrf2 Activators

©Reata Pharmaceuticals, Inc.
Proprietary Reata Nrf2 activator bound to Keap1
PDB Code 5DAF

We are developing Nrf2 activators to treat chronic diseases characterized by mitochondrial dysfunction, oxidative stress, and chronic inflammation.

Mitochondria are often called the "powerhouses" of the cell because of their ability to efficiently generate the energy cells need in the form of adenosine triphosphate (ATP). However, mitochondria also play an important role in inflammation. As part of the inflammatory response, cells undergo a "metabolic shift" that reduces ATP production by the mitochondria (2). Instead, mitochondria produce reactive oxygen species (ROS) and other byproducts that amplify inflammation (3-5). This metabolic shift is meant to be a temporary response to infection or injury. Once resolved, it is critical that mitochondrial metabolism returns to its normal state, ROS are neutralized, and inflammatory processes are turned off (6).

kidney

Bardoxolone Methyl in Chronic Kidney Disease (CKD)

Bardoxolone methyl is an Nrf2 activator currently being investigated in clinical trials for the treatment of patients with different forms of chronic kidney disease.

Inflammation—initiated by a variety of pathogenic processes, including diabetes, systemic hypertension, IgA deposition, and genetic mutations—drives kidney function decline (12). At the molecular level, these pathogenic processes induce mitochondrial dysfunction, decrease ATP production, and promote production of ROS and pro-inflammatory signaling mediators that initiate and amplify inflammatory pathways in glomerular endothelial cells, mesangial cells, and podocytes, while also recruiting activated macrophages and other inflammatory effector cells to the renal interstitium. At the physiological level, chronic activation of pro-inflammatory pathways in these kidney cells leads to a reduction in the glomerular filtration rate (GFR) (13-15).

Bard in CKD
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In preclinical models, bardoxolone methyl suppresses inflammatory pathways that contribute to kidney function loss by increasing Nrf2 activity (1, 7-11). The beneficial activity of bardoxolone methyl and analogs has been observed in several nonclinical models of CKD, including CKD caused by diabetes, hypertension, autoimmune disease, nephron loss, and nephrosis (7, 9-11, 16, 17). In these models, bardoxolone methyl and analogs suppress inflammation and fibrosis (7, 9-11), reduce glomerulosclerosis (10, 11, 17), prevent tubulointerstitial damage (7, 9-11), and improve kidney function (7, 10, 16, 17).

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References

References

  1. Shelton, L. M., Lister, A., Walsh, J., Jenkins, R. E., Wong, M. H., Rowe, C., Ricci, E., Ressel, L., Fang, Y., Demougin, P., Vukojevic, V., O'Neill, P. M., Goldring, C. E., Kitteringham, N. R., Park, B. K., Odermatt, A., and Copple, I. M. (2015) Integrated transcriptomic and proteomic analyses uncover regulatory roles of Nrf2 in the kidney. Kidney Int 88, 1261-1273
  2. Breda, C. N. S., Davanzo, G. G., Basso, P. J., Saraiva Camara, N. O., and Moraes-Vieira, P. M. M. (2019) Mitochondria as central hub of the immune system. Redox Biol 26, 101255
  3. Banoth, B., and Cassel, S. L. (2018) Mitochondria in innate immune signaling. Transl Res 202, 52-68
  4. Jung, J., Zeng, H., and Horng, T. (2019) Metabolism as a guiding force for immunity. Nat Cell Biol 21, 85-93
  5. West, A. P., Brodsky, I. E., Rahner, C., Woo, D. K., Erdjument-Bromage, H., Tempst, P., Walsh, M. C., Choi, Y., Shadel, G. S., and Ghosh, S. (2011) TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 472, 476-480
  6. Gilroy, D., and De Maeyer, R. (2015) New insights into the resolution of inflammation. Semin Immunol 27, 161-168
  7. Nagasu, H., Sogawa, Y., Kidokoro, K., Itano, S., Yamamoto, T., Satoh, M., Sasaki, T., Suzuki, T., Yamamoto, M., Wigley, W. C., Proksch, J. W., Meyer, C. J., and Kashihara, N. (2019) Bardoxolone methyl analog attenuates proteinuria-induced tubular damage by modulating mitochondrial function. FASEB J 33, 12253-12263
  8. Camer, D., Yu, Y., Szabo, A., Wang, H., Dinh, C. H., and Huang, X. F. (2016) Bardoxolone methyl prevents the development and progression of cardiac and renal pathophysiologies in mice fed a high-fat diet. Chem. Biol. Interact 243, 10-18
  9. Hisamichi, M., Kamijo-Ikemori, A., Sugaya, T., Hoshino, S., Kimura, K., and Shibagaki, Y. (2018) Role of bardoxolone methyl, a nuclear factor erythroid 2-related factor 2 activator, in aldosterone- and salt-induced renal injury. Hypertens. Res 41, 8-17
  10. Aminzadeh, M. A., Reisman, S. A., Vaziri, N. D., Khazaeli, M., Yuan, J., and Meyer, C. J. (2014) The synthetic triterpenoid RTA dh404 (CDDO-dhTFEA) restores Nrf2 activity and attenuates oxidative stress, inflammation, and fibrosis in rats with chronic kidney disease. Xenobiotica 44, 570-578
  11. Tan, S. M., Sharma, A., Stefanovic, N., Yuen, D. Y., Karagiannis, T. C., Meyer, C., Ward, K. W., Cooper, M. E., and de Haan, J. B. (2014) Derivative of bardoxolone methyl, dh404, in an inverse dose-dependent manner lessens diabetes-associated atherosclerosis and improves diabetic kidney disease. Diabetes 63, 3091-3103
  12. Stenvinkel, P., Chertow, G. M., Devarajan, P., Levin, A., Andreoli, S. P., Bangalore, S., and Warady, B. A. (2021) Chronic Inflammation in Chronic Kidney Disease Progression: Role of Nrf2. Kidney Int Rep 6, 1775-1787
  13. Amdur, R. L., Feldman, H. I., Gupta, J., Yang, W., Kanetsky, P., Shlipak, M., Rahman, M., Lash, J. P., Townsend, R. R., Ojo, A., Roy-Chaudhury, A., Go, A. S., Joffe, M., He, J., Balakrishnan, V. S., Kimmel, P. L., Kusek, J. W., and Raj, D. S. (2016) Inflammation and Progression of CKD: The CRIC Study. Clin J Am Soc Nephrol 11, 1546-1556
  14. Puthumana, J., Thiessen-Philbrook, H., Xu, L., Coca, S. G., Garg, A. X., Himmelfarb, J., Bhatraju, P. K., Ikizler, T. A., Siew, E. D., Ware, L. B., Liu, K. D., Go, A. S., Kaufman, J. S., Kimmel, P. L., Chinchilli, V. M., Cantley, L. G., and Parikh, C. R. (2021) Biomarkers of inflammation and repair in kidney disease progression. J Clin Invest 131
  15. Lv, W., Booz, G. W., Wang, Y., Fan, F., and Roman, R. J. (2018) Inflammation and renal fibrosis: Recent developments on key signaling molecules as potential therapeutic targets. Eur. J. Pharmacol 820, 65-76
  16. Chin, M., Lee, C. Y., Chuang, J. C., Bumeister, R., Wigley, W. C., Sonis, S. T., Ward, K. W., and Meyer, C. (2013) Bardoxolone methyl analogs RTA 405 and dh404 are well tolerated and exhibit efficacy in rodent models of Type 2 diabetes and obesity. Am. J. Physiol Renal Physiol 304, F1438-F1446
  17. Wu, T., Ye, Y., Min, S. Y., Zhu, J., Khobahy, E., Zhou, J., Yan, M., Hemachandran, S., Pathak, S., Zhou, X. J., Andreeff, M., and Mohan, C. (2014) Prevention of murine lupus nephritis by targeting multiple signaling axes and oxidative stress using a synthetic triterpenoid. Arthritis Rheumatol 66, 3129-3139
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