Nrf2 Activators

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

Bard and Omav
Click to Enlarge

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

Bardoxolone methyl and omaveloxolone are investigational Nrf2 activators that selectively bind to Keap1 (1, 2), a protein that governs the activity of Nrf2 in response to cellular stress. By binding to Keap1, bardoxolone methyl and omaveloxolone stabilize Nrf2 and increase its activity in the nucleus (3, 4), where it controls the expression of a network of genes that coordinate many processes that help mitigate inflammation, reduce oxidative stress, and restore mitochondrial function (5-8).

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 (9). Instead, mitochondria produce reactive oxygen species (ROS) and other byproducts that amplify inflammation (10-12). 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 (13).

In many chronic, autoimmune, and genetic diseases, the resolution of inflammation fails to occur and ultimately leads to persistent mitochondrial dysfunction and excessive production of ROS and pro-inflammatory signaling molecules (13, 14). Chronic inflammation and altered mitochondrial metabolism contribute to abnormal cellular proliferation, tissue remodeling, fibrosis, and loss of organ function (15-18).

Nrf2 is a key player in the resolution of inflammation (19), and its activity is often suppressed in chronic disease (20-26). Several molecules that are naturally produced during the resolution of inflammation are activators of Nrf2, underscoring the importance of a well-timed Nrf2 response in this restorative process (27-30). Our Nrf2 activators have been shown to suppress inflammation, reduce oxidative stress, and restore mitochondrial function, resulting in broad anti-inflammatory and antifibrotic activity in nonclinical disease models (31-42).

Since mitochondrial dysfunction, oxidative stress, and chronic inflammation are features of many diseases, Nrf2 activators may have many potential clinical applications. Both bardoxolone methyl and omaveloxolone are in late-stage development for chronic kidney disease and Friedreich's ataxia, respectively.

Nrf2 Activator MOA
Click to Enlarge

nrf2 triangle indications
Click to Enlarge

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 (43). 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) (44-46).

Bard in CKD
Click to Enlarge

In preclinical models, bardoxolone methyl suppresses inflammatory pathways that contribute to kidney function loss by increasing Nrf2 activity (4, 32-36). 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 (32, 34-36, 47, 48). In these models, bardoxolone methyl and analogs suppress inflammation and fibrosis (32, 34-36), reduce glomerulosclerosis (35, 36, 48), prevent tubulointerstitial damage (32, 34-36), and improve kidney function (32, 35, 47, 48).

Follow the links to:

Omaveloxolone in Neurological Diseases

Omaveloxolone is an Nrf2 activator currently being investigated in clinical trials for the treatment of patients with Friedreich’s ataxia (FA). FA is a neurodegenerative disease characterized by mitochondrial dysfunction, increased sensitivity to oxidative stress, and impaired mitochondrial ATP production (49). Omaveloxolone has been shown activate Nrf2 and improve several disease parameters in nonclinical models of FA (37) (and Reata unpublished data).

Mitochondrial dysfunction and neuroinflammation are common features of many neurological diseases (17). Omaveloxolone and analogs have shown activity in numerous nonclinical models (31, 37-42, 50, 51), as well as patient biopsy samples (37. 50), and we believe the pharmacology is applicable to a broad set of neurological diseases, including other movements disorders, such as progressive supranuclear palsy (PSP), Parkinson’s disease, and Huntington’s disease, as well as diseases that affect neuromuscular function and memory.

Omav in Neuro
Click to Enlarge

In nonclinical studies, our Nrf2 activators reduced seizure frequency in refractory, progressive epilepsy models and restored mitochondrial function in models of FA (37), ALS (40), familial (51) and sporadic Parkinson’s disease (Reata unpublished data), and frontotemporal dementia (50). We believe that omaveloxolone has the potential to treat a number of neurological and neuromuscular diseases that currently have few or no effective therapies.

Follow the links to:

brain

References

  1. 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
  2. Huerta, C., Jiang, X., Trevino, I., Bender, C. F., Ferguson, D. A., Probst, B., Swinger, K. K., Stoll, V. S., Thomas, P. J., Dulubova, I., Visnick, M., and Wigley, W. C. (2016) Characterization of novel small-molecule NRF2 activators: Structural and biochemical validation of stereospecific KEAP1 binding. Biochim Biophys Acta 1860, 2537-2552
  3. Yates, M. S., Tauchi, M., Katsuoka, F., Flanders, K. C., Liby, K. T., Honda, T., Gribble, G. W., Johnson, D. A., Johnson, J. A., Burton, N. C., Guilarte, T. R., Yamamoto, M., Sporn, M. B., and Kensler, T. W. (2007) Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Mol Cancer Ther 6, 154-162
  4. 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
  5. Yamamoto, M., Kensler, T. W., and Motohashi, H. (2018) The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis. Physiol Rev 98, 1169-1203
  6. 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
  7. Holmstrom, K. M., Kostov, R. V., and Dinkova-Kostova, A. T. (2016) The multifaceted role of Nrf2 in mitochondrial function. Curr Opin Toxicol 1, 80-91
  8. Kobayashi, E. H., Suzuki, T., Funayama, R., Nagashima, T., Hayashi, M., Sekine, H., Tanaka, N., Moriguchi, T., Motohashi, H., Nakayama, K., and Yamamoto, M. (2016) Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun 7, 11624
  9. 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
  10. Banoth, B., and Cassel, S. L. (2018) Mitochondria in innate immune signaling. Transl Res 202, 52-68
  11. Jung, J., Zeng, H., and Horng, T. (2019) Metabolism as a guiding force for immunity. Nat Cell Biol 21, 85-93
  12. 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
  13. Gilroy, D., and De Maeyer, R. (2015) New insights into the resolution of inflammation. Semin Immunol 27, 161-168
  14. Dela Cruz, C. S., and Kang, M. J. (2018) Mitochondrial dysfunction and damage associated molecular patterns (DAMPs) in chronic inflammatory diseases. Mitochondrion 41, 37-44
  15. Liu, Y. (2011) Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol 7, 684-696
  16. Inoue, T., Maekawa, H., and Inagi, R. (2019) Organelle crosstalk in the kidney. Kidney Int 95, 1318-1325
  17. Wilkins, H. M., Weidling, I. W., Ji, Y., and Swerdlow, R. H. (2017) Mitochondria-Derived Damage-Associated Molecular Patterns in Neurodegeneration. Front Immunol 8, 508
  18. Lynch, M. A. (2020) Can the emerging field of immunometabolism provide insights into neuroinflammation? Prog Neurobiol 184, 101719
  19. Friedli, O., and Freigang, S. (2017) Cyclopentenone-containing oxidized phospholipids and their isoprostanes as pro-resolving mediators of inflammation. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1862, 382-392
  20. Lu, M., Wang, P., Qiao, Y., Jiang, C., Ge, Y., Flickinger, B., Malhotra, D. K., Dworkin, L. D., Liu, Z., and Gong, R. (2019) GSK3β-mediated Keap1-independent regulation of Nrf2 antioxidant response: A molecular rheostat of acute kidney injury to chronic kidney disease transition. Redox Biol 26, 101275
  21. Feng, Y.-L., Chen, H., Chen, D.-Q., Vaziri, N. D., Su, W., Ma, S.-X., Shang, Y.-Q., Mao, J.-R., Yu, X.-Y., Zhang, L., Guo, Y., and Zhao, Y.-Y. (2019) Activated NF-κB/Nrf2 and Wnt/β-catenin pathways are associated with lipid metabolism in CKD patients with microalbuminuria and macroalbuminuria. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1865, 2317-2332
  22. Lu, Y., Sun, Y., Liu, Z., Lu, Y., Zhu, X., Lan, B., Mi, Z., Dang, L., Li, N., Zhan, W., Tan, L., Pi, J., Xiong, H., Zhang, L., and Chen, Y. (2020) Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease. Sci Transl Med 12
  23. Kanninen, K., Malm, T. M., Jyrkkänen, H. K., Goldsteins, G., Keksa-Goldsteine, V., Tanila, H., Yamamoto, M., Ylä-Herttuala, S., Levonen, A. L., and Koistinaho, J. (2008) Nuclear factor erythroid 2-related factor 2 protects against beta amyloid. Mol Cell Neurosci 39, 302-313
  24. Sarlette, A., Krampfl, K., Grothe, C., Neuhoff, N. v., Dengler, R., and Petri, S. (2008) Nuclear Erythroid 2-Related Factor 2-Antioxidative Response Element Signaling Pathway in Motor Cortex and Spinal Cord in Amyotrophic Lateral Sclerosis. Journal of Neuropathology & Experimental Neurology 67, 1055-1062
  25. Paupe, V., Dassa, E. P., Goncalves, S., Auchère, F., Lönn, M., Holmgren, A., and Rustin, P. (2009) Impaired nuclear Nrf2 translocation undermines the oxidative stress response in Friedreich ataxia. PloS one 4, e4253-e4253
  26. Petrillo, S., Piermarini, E., Pastore, A., Vasco, G., Schirinzi, T., Carrozzo, R., Bertini, E., and Piemonte, F. (2017) Nrf2-Inducers Counteract Neurodegeneration in Frataxin-Silenced Motor Neurons: Disclosing New Therapeutic Targets for Friedreich's Ataxia. Int J Mol Sci 18, 2173
  27. Mills, E. L., Ryan, D. G., Prag, H. A., Dikovskaya, D., Menon, D., Zaslona, Z., Jedrychowski, M. P., Costa, A. S. H., Higgins, M., Hams, E., Szpyt, J., Runtsch, M. C., King, M. S., McGouran, J. F., Fischer, R., Kessler, B. M., McGettrick, A. F., Hughes, M. M., Carroll, R. G., Booty, L. M., Knatko, E. V., Meakin, P. J., Ashford, M. L. J., Modis, L. K., Brunori, G., Sevin, D. C., Fallon, P. G., Caldwell, S. T., Kunji, E. R. S., Chouchani, E. T., Frezza, C., Dinkova-Kostova, A. T., Hartley, R. C., Murphy, M. P., and O'Neill, L. A. (2018) Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113-117
  28. Shibata, T. (2015) 15-Deoxy-Delta(1)(2),(1)(4)-prostaglandin J(2) as an electrophilic mediator. Biosci Biotechnol Biochem 79, 1044-1049
  29. Khoo, N. K. H., and Schopfer, F. J. (2019) Nitrated fatty acids: from diet to disease. Curr Opin Physiol 9, 67-72
  30. Rojas-Morales, P., Pedraza-Chaverri, J., and Tapia, E. (2020) Ketone bodies, stress response, and redox homeostasis. Redox biology 29, 101395-101395
  31. Shekh-Ahmad, T., Eckel, R., Dayalan Naidu, S., Higgins, M., Yamamoto, M., Dinkova-Kostova, A. T., Kovac, S., Abramov, A. Y., and Walker, M. C. (2018) KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain 141, 1390-1403
  32. 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
  33. 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
  34. 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
  35. 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
  36. 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
  37. Abeti, R., Baccaro, A., Esteras, N., and Giunti, P. (2018) Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich's Ataxia Models. Front Cell Neurosci 12, 188
  38. Dumont, M., Wille, E., Calingasan, N. Y., Tampellini, D., Williams, C., Gouras, G. K., Liby, K., Sporn, M., Nathan, C., Flint Beal, M., and Lin, M. T. (2009) Triterpenoid CDDO-methylamide improves memory and decreases amyloid plaques in a transgenic mouse model of Alzheimer's disease. J Neurochem 109, 502-512
  39. Pareek, T. K., Belkadi, A., Kesavapany, S., Zaremba, A., Loh, S. L., Bai, L., Cohen, M. L., Meyer, C., Liby, K. T., Miller, R. H., Sporn, M. B., and Letterio, J. J. (2011) Triterpenoid modulation of IL-17 and Nrf-2 expression ameliorates neuroinflammation and promotes remyelination in autoimmune encephalomyelitis. Sci Rep 1, 201
  40. Neymotin, A., Calingasan, N. Y., Wille, E., Naseri, N., Petri, S., Damiano, M., Liby, K. T., Risingsong, R., Sporn, M., Beal, M. F., and Kiaei, M. (2011) Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis. Free Radic Biol Med 51, 88-96
  41. Kaidery, N. A., Banerjee, R., Yang, L., Smirnova, N. A., Hushpulian, D. M., Liby, K. T., Williams, C. R., Yamamoto, M., Kensler, T. W., Ratan, R. R., Sporn, M. B., Beal, M. F., Gazaryan, I. G., and Thomas, B. (2013) Targeting Nrf2-mediated gene transcription by extremely potent synthetic triterpenoids attenuate dopaminergic neurotoxicity in the MPTP mouse model of Parkinson's disease. Antioxidants & redox signaling 18, 139-157
  42. Stack, C., Ho, D., Wille, E., Calingasan, N. Y., Williams, C., Liby, K., Sporn, M., Dumont, M., and Beal, M. F. (2010) Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington's disease. Free Radic Biol Med 49, 147-158
  43. 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
  44. 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
  45. 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
  46. 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
  47. 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
  48. 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
  49. Clay, A., Hearle, P., Schadt, K., and Lynch, D. R. (2019) New developments in pharmacotherapy for Friedreich ataxia. Expert Opin Pharmacother 20, 1855-1867
  50. Bartolome, F., Esteras, N., Martin-Requero, A., Boutoleau-Bretonniere, C., Vercelletto, M., Gabelle, A., Le Ber, I., Honda, T., Dinkova-Kostova, A. T., Hardy, J., Carro, E., and Abramov, A. Y. (2017) Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates. Sci Rep 7, 1666
  51. Dinkova-Kostova, A. T., Baird, L., Holmstrom, K. M., Meyer, C. J., and Abramov, A. Y. (2015) The spatiotemporal regulation of the Keap1-Nrf2 pathway and its importance in cellular bioenergetics. Biochem Soc Trans 43, 602-610
back to top
Blue Bonnets