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Bardoxolone methyl

Description of Bardoxolone methyl: Bardoxolone methyl (also known as “RTA 402” and “CDDO-methyl ester”) is an orally-available first-in-class synthetic triterpenoid belonging to the antioxidant inflammation modulator (AIM) class. It is the most potent known inducer of the Nrf2 pathway to enter clinical development and works to suppress both oxidative stress and inflammation.  Bardoxolone methyl is currently being developed by Reata Pharmaceuticals, Inc. in partnership with Abbott Laboratories and Kyowa Hakko Kirin, for the treatment of advanced chronic kidney disease (CKD) in type 2 diabetes mellitus patients. (Source: http://en.wikipedia.org/wiki/Bardoxolone_methyl).

Current developer:    Reata Pharmaceuticals Inc; Abbott Laboratories;  and Kyowa Hakko Kirin

Bardoxolone methyl, previously known as RTA 402, is the lead molecule emerging from Reata’s platform of Antioxidant Inflammation Modulators (AIMs). The AIMs are the most potent known inducers of Nrf2, an important emerging biological target that controls the production of many of the body’s antioxidant and detoxification enzymes. There is a strong biological rationale for the use of agents targeting Nrf2 to treat renal and cardiovascular disease. Chronic oxidative stress-mediated inflammation is known to play an important role in the degeneration of kidney function. Based on data from three clinical studies demonstrating improvements in patients’ markers of kidney function and potential disease-modifying activity, bardoxolone has been advanced to late-stage clinical development and is currently undergoing a pivotal Phase 2b trial in chronic kidney disease patients with type 2 diabetes mellitus.

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2: Ahmad R, Liu S, Weisberg E, Nelson E, Galinsky I, Meyer C, Kufe D, Kharbanda S, Stone R. Combining the FLT3 inhibitor PKC412 and the triterpenoid CDDO-Me synergistically induces apoptosis in acute myeloid leukemia with the internal tandem duplication mutation. Mol Cancer Res. 2010 Jul;8(7):986-93. Epub 2010 Jun 22. PubMed PMID: 20571062; PubMed Central PMCID: PMC2905481.

3: To C, Shilton BH, Di Guglielmo GM. Synthetic triterpenoids target the ARP2/3 complex and inhibit branched actin polymerization. J Biol Chem. 2010 Jun 21. [Epub ahead of print] PubMed PMID: 20566646.

4: Jutooru I, Chadalapaka G, Abdelrahim M, Basha MR, Samudio I, Konopleva M, Andreeff M, Safe S. Methyl 2-cyano-3,12-dioxooleana-1,9-dien-28-oate decreases specificity protein transcription factors and inhibits pancreatic tumor growth: role of microRNA-27a. Mol Pharmacol. 2010 Aug;78(2):226-36. Epub 2010 May 20. PubMed PMID: 20488920.

5: Ryu K, Susa M, Choy E, Yang C, Hornicek FJ, Mankin HJ, Duan Z. Oleanane triterpenoid CDDO-Me induces apoptosis in multidrug resistant osteosarcoma cells through inhibition of Stat3 pathway. BMC Cancer. 2010 May 10;10:187. PubMed PMID: 20459702; PubMed Central PMCID: PMC2874784.

6: Gao X, Deeb D, Hao J, Liu Y, Arbab AS, Dulchavsky SA, Gautam SC. Synthetic triterpenoids inhibit growth, induce apoptosis and suppress pro-survival Akt, mTOR and NF-{kappa}B signaling proteins in colorectal cancer cells. Anticancer Res. 2010 Mar;30(3):785-92. PubMed PMID: 20392997.

7: Yang C, Hornicek FJ, Wood KB, Schwab JH, Choy E, Mankin H, Duan Z. Blockage of Stat3 With CDDO-Me Inhibits Tumor Cell Growth in Chordoma. Spine (Phila Pa 1976). 2010 Apr 9. [Epub ahead of print] PubMed PMID: 20386502.

8: Olsen AM, Eisenberg BL, Kuemmerle NB, Flanagan AJ, Morganelli PM, Lombardo PS, Swinnen JV, Kinlaw WB. Fatty acid synthesis is a therapeutic target in human liposarcoma. Int J Oncol. 2010 May;36(5):1309-14. PubMed PMID: 20372807.

9: Li M, Sun K, Redelman D, Welniak LA, Murphy WJ. The triterpenoid CDDO-Me delays murine acute graft-versus-host disease with the preservation of graft-versus-tumor effects after allogeneic bone marrow transplantation. Biol Blood Marrow Transplant. 2010 Jun;16(6):739-50. Epub 2010 Mar 23. PubMed PMID: 20338256; PubMed Central PMCID: PMC2866806.

10: Kidd S, Caldwell L, Dietrich M, Samudio I, Spaeth EL, Watson K, Shi Y, Abbruzzese J, Konopleva M, Andreeff M, Marini FC. Mesenchymal stromal cells alone or expressing interferon-beta suppress pancreatic tumors in vivo, an effect countered by anti-inflammatory treatment. Cytotherapy. 2010 Mar 15. [Epub ahead of print] PubMed PMID: 20230221.

11: Nagaraj S, Youn JI, Weber H, Iclozan C, Lu L, Cotter MJ, Meyer C, Becerra CR, Fishman M, Antonia S, Sporn MB, Liby KT, Rawal B, Lee JH, Gabrilovich DI. Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer. Clin Cancer Res. 2010 Mar 15;16(6):1812-23. Epub 2010 Mar 9. PubMed PMID: 20215551; PubMed Central PMCID: PMC2840181.

12: Ryu K, Choy E, Yang C, Susa M, Hornicek FJ, Mankin H, Duan Z. Activation of signal transducer and activator of transcription 3 (Stat3) pathway in osteosarcoma cells and overexpression of phosphorylated-Stat3 correlates with poor prognosis. J Orthop Res. 2010 Jul;28(7):971-8. PubMed PMID: 20063378.

13: Liby K, Risingsong R, Royce DB, Williams CR, Ma T, Yore MM, Sporn MB. Triterpenoids CDDO-methyl ester or CDDO-ethyl amide and rexinoids LG100268 or NRX194204 for prevention and treatment of lung cancer in mice. Cancer Prev Res (Phila Pa). 2009 Dec;2(12):1050-8. Epub 2009 Dec 1. PubMed PMID: 19952361; PubMed Central PMCID: PMC2818234.

14: Deeb D, Gao X, Jiang H, Janic B, Arbab AS, Rojanasakul Y, Dulchavsky SA, Gautam SC. Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells through a ROS-dependent mechanism. Biochem Pharmacol. 2010 Feb 1;79(3):350-60. Epub 2009 Sep 24. PubMed PMID: 19782051; PubMed Central PMCID: PMC2822351.

15: Petronelli A, Pannitteri G, Testa U. Triterpenoids as new promising anticancer drugs. Anticancer Drugs. 2009 Nov;20(10):880-92. Review. PubMed PMID: 19745720.

16: Ghavami S, Hashemi M, Ande SR, Yeganeh B, Xiao W, Eshraghi M, Bus CJ, Kadkhoda K, Wiechec E, Halayko AJ, Los M. Apoptosis and cancer: mutations within caspase genes. J Med Genet. 2009 Aug;46(8):497-510. Epub 2009 Jun 7. Review. PubMed PMID: 19505876.

17: Sogno I, Vannini N, Lorusso G, Cammarota R, Noonan DM, Generoso L, Sporn MB, Albini A. Anti-angiogenic activity of a novel class of chemopreventive compounds: oleanic acid terpenoids. Recent Results Cancer Res. 2009;181:209-12. Review. PubMed PMID: 19213570.

18: Deeb D, Gao X, Jiang H, Dulchavsky SA, Gautam SC. Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells by independently targeting pro-survival Akt and mTOR. Prostate. 2009 Jun 1;69(8):851-60. PubMed PMID: 19189297.

19: Zou W, Yue P, Khuri FR, Sun SY. Coupling of endoplasmic reticulum stress to CDDO-Me-induced up-regulation of death receptor 5 via a CHOP-dependent mechanism involving JNK activation. Cancer Res. 2008 Sep 15;68(18):7484-92. PubMed PMID: 18794136; PubMed Central PMCID: PMC2597446.

20: Venè R, Larghero P, Arena G, Sporn MB, Albini A, Tosetti F. Glycogen synthase kinase 3beta regulates cell death induced by synthetic triterpenoids. Cancer Res. 2008 Sep 1;68(17):6987-96. PubMed PMID: 18757413.

21: Liby K, Risingsong R, Royce DB, Williams CR, Yore MM, Honda T, Gribble GW, Lamph WW, Vannini N, Sogno I, Albini A, Sporn MB. Prevention and treatment of experimental estrogen receptor-negative mammary carcinogenesis by the synthetic triterpenoid CDDO-methyl Ester and the rexinoid LG100268. Clin Cancer Res. 2008 Jul 15;14(14):4556-63. PubMed PMID: 18628471.

22: Gao X, Deeb D, Danyluk A, Media J, Liu Y, Dulchavsky SA, Gautam SC. Immunomodulatory activity of synthetic triterpenoids: inhibition of lymphocyte proliferation, cell-mediated cytotoxicity, and cytokine gene expression through suppression of NF-kappaB. Immunopharmacol Immunotoxicol. 2008;30(3):581-600. PubMed PMID: 18608528.

23: Duan Z, Ames RY, Ryan M, Hornicek FJ, Mankin H, Seiden MV. CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells. Cancer Chemother Pharmacol. 2009 Mar;63(4):681-9. Epub 2008 Jun 28. PubMed PMID: 18587580; PubMed Central PMCID: PMC2875930.

24: Samudio I, Kurinna S, Ruvolo P, Korchin B, Kantarjian H, Beran M, Dunner K Jr, Kondo S, Andreeff M, Konopleva M. Inhibition of mitochondrial metabolism by methyl-2-cyano-3,12-dioxooleana-1,9-diene-28-oate induces apoptotic or autophagic cell death in chronic myeloid leukemia cells. Mol Cancer Ther. 2008 May;7(5):1130-9. PubMed PMID: 18483301; PubMed Central PMCID: PMC2396196.

25: Tran TA, McCoy MK, Sporn MB, Tansey MG. The synthetic triterpenoid CDDO-methyl ester modulates microglial activities, inhibits TNF production, and provides dopaminergic neuroprotection. J Neuroinflammation. 2008 May 12;5:14. PubMed PMID: 18474101; PubMed Central PMCID: PMC2396606.

26: Deeb D, Gao X, Dulchavsky SA, Gautam SC. CDDO-Me inhibits proliferation, induces apoptosis, down-regulates Akt, mTOR, NF-kappaB and NF-kappaB-regulated antiapoptotic and proangiogenic proteins in TRAMP prostate cancer cells. J Exp Ther Oncol. 2008;7(1):31-9. PubMed PMID: 18472640.

27: Elsawa SF, Novak AJ, Grote D, Konopleva M, Andreeff M, Witzig TE, Ansell SM. CDDO-imidazolide mediated inhibition of malignant cell growth in Waldenström macroglobulinemia. Leuk Res. 2008 Dec;32(12):1895-902. Epub 2008 May 12. PubMed PMID: 18468679; PubMed Central PMCID: PMC2776029.

28: Hyer ML, Shi R, Krajewska M, Meyer C, Lebedeva IV, Fisher PB, Reed JC. Apoptotic activity and mechanism of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic-acid and related synthetic triterpenoids in prostate cancer. Cancer Res. 2008 Apr 15;68(8):2927-33. PubMed PMID: 18413762.

29: Ahmad R, Raina D, Meyer C, Kufe D. Triterpenoid CDDO-methyl ester inhibits the Janus-activated kinase-1 (JAK1)-->signal transducer and activator of transcription-3 (STAT3) pathway by direct inhibition of JAK1 and STAT3. Cancer Res. 2008 Apr 15;68(8):2920-6. PubMed PMID: 18413761.

30: Alabran JL, Cheuk A, Liby K, Sporn M, Khan J, Letterio J, Leskov KS. Human neuroblastoma cells rapidly enter cell cycle arrest and apoptosis following exposure to C-28 derivatives of the synthetic triterpenoid CDDO. Cancer Biol Ther. 2008 May;7(5):709-17. Epub 2008 May 7. PubMed PMID: 18277094; PubMed Central PMCID: PMC2727860.

31: Zou W, Chen S, Liu X, Yue P, Sporn MB, Khuri FR, Sun SY. c-FLIP downregulation contributes to apoptosis induction by the novel synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9-dien-28-oate (CDDO-Me) in human lung cancer cells. Cancer Biol Ther. 2007 Oct;6(10):1614-20. Epub 2007 Jul 19. PubMed PMID: 18253090.

32: Tabe Y, Konopleva M, Kondo Y, Contractor R, Tsao T, Konoplev S, Shi Y, Ling X, Watt JC, Tsutsumi-Ishii Y, Ohsaka A, Nagaoka I, Issa JP, Kogan SC, Andreeff M. PPARgamma-active triterpenoid CDDO enhances ATRA-induced differentiation in APL. Cancer Biol Ther. 2007 Dec;6(12):1967-77. Epub 2007 Sep 4. PubMed PMID: 18075297.

33: Vannini N, Lorusso G, Cammarota R, Barberis M, Noonan DM, Sporn MB, Albini A. The synthetic oleanane triterpenoid, CDDO-methyl ester, is a potent antiangiogenic agent. Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3139-46. Epub 2007 Dec 7. PubMed PMID: 18065492.

34: Kong G, Wang D, Wang H, Wu J, Bielawski J, Konopleva M, Andreeff M, Ruvolo PP, Maurer BJ. Synthetic triterpenoids have cytotoxicity in pediatric acute lymphoblastic leukemia cell lines but cytotoxicity is independent of induced ceramide increase in MOLT-4 cells. Leukemia. 2008 Jun;22(6):1258-62. Epub 2007 Nov 22. PubMed PMID: 18033322.

35: Deeb D, Gao X, Dulchavsky SA, Gautam SC. CDDO-me induces apoptosis and inhibits Akt, mTOR and NF-kappaB signaling proteins in prostate cancer cells. Anticancer Res. 2007 Sep-Oct;27(5A):3035-44. PubMed PMID: 17970042.

36: Thimmulappa RK, Fuchs RJ, Malhotra D, Scollick C, Traore K, Bream JH, Trush MA, Liby KT, Sporn MB, Kensler TW, Biswal S. Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils. Antioxid Redox Signal. 2007 Nov;9(11):1963-70. PubMed PMID: 17822364; PubMed Central PMCID: PMC2396226.

37: Ling X, Konopleva M, Zeng Z, Ruvolo V, Stephens LC, Schober W, McQueen T, Dietrich M, Madden TL, Andreeff M. The novel triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid inhibits metastatic murine breast tumor growth through inactivation of STAT3 signaling. Cancer Res. 2007 May 1;67(9):4210-8. Erratum in: Cancer Res. 2008 Jun 15;68(12):4958. PubMed PMID: 17483332.

38: Liby K, Royce DB, Williams CR, Risingsong R, Yore MM, Honda T, Gribble GW, Dmitrovsky E, Sporn TA, Sporn MB. The synthetic triterpenoids CDDO-methyl ester and CDDO-ethyl amide prevent lung cancer induced by vinyl carbamate in A/J mice. Cancer Res. 2007 Mar 15;67(6):2414-9. PubMed PMID: 17363558.

39: Gao X, Deeb D, Jiang H, Liu Y, Dulchavsky SA, Gautam SC. Synthetic triterpenoids inhibit growth and induce apoptosis in human glioblastoma and neuroblastoma cells through inhibition of prosurvival Akt, NF-kappaB and Notch1 signaling. J Neurooncol. 2007 Sep;84(2):147-57. Epub 2007 Mar 15. PubMed PMID: 17361329.

40: Yates MS, Tauchi M, Katsuoka F, Flanders KC, Liby KT, Honda T, Gribble GW, Johnson DA, Johnson JA, Burton NC, Guilarte TR, Yamamoto M, Sporn MB, Kensler TW. Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Mol Cancer Ther. 2007 Jan;6(1):154-62. PubMed PMID: 17237276.

41: Ahmad R, Raina D, Meyer C, Kharbanda S, Kufe D. Triterpenoid CDDO-Me blocks the NF-kappaB pathway by direct inhibition of IKKbeta on Cys-179. J Biol Chem. 2006 Nov 24;281(47):35764-9. Epub 2006 Sep 24. PubMed PMID: 16998237.

42: Yue P, Zhou Z, Khuri FR, Sun SY. Depletion of intracellular glutathione contributes to JNK-mediated death receptor 5 upregulation and apoptosis induction by the novel synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9-dien-28-oate (CDDO-Me). Cancer Biol Ther. 2006 May;5(5):492-7. Epub 2006 May 2. PubMed PMID: 16582599.

43: Shishodia S, Sethi G, Konopleva M, Andreeff M, Aggarwal BB. A synthetic triterpenoid, CDDO-Me, inhibits IkappaBalpha kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor kappaB-regulated gene products in human leukemic cells. Clin Cancer Res. 2006 Mar 15;12(6):1828-38. PubMed PMID: 16551868.

44: Samudio I, Konopleva M, Pelicano H, Huang P, Frolova O, Bornmann W, Ying Y, Evans R, Contractor R, Andreeff M. A novel mechanism of action of methyl-2-cyano-3,12 dioxoolean-1,9 diene-28-oate: direct permeabilization of the inner mitochondrial membrane to inhibit electron transport and induce apoptosis. Mol Pharmacol. 2006 Apr;69(4):1182-93. Epub 2006 Jan 12. PubMed PMID: 16410408.

45: Konopleva M, Contractor R, Kurinna SM, Chen W, Andreeff M, Ruvolo PP. The novel triterpenoid CDDO-Me suppresses MAPK pathways and promotes p38 activation in acute myeloid leukemia cells. Leukemia. 2005 Aug;19(8):1350-4. PubMed PMID: 15931262.

46: Chintharlapalli S, Papineni S, Konopleva M, Andreef M, Samudio I, Safe S. 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid and related compounds inhibit growth of colon cancer cells through peroxisome proliferator-activated receptor gamma-dependent and -independent pathways. Mol Pharmacol. 2005 Jul;68(1):119-28. Epub 2005 Mar 29. PubMed PMID: 15798084.

47: Zou W, Liu X, Yue P, Zhou Z, Sporn MB, Lotan R, Khuri FR, Sun SY. c-Jun NH2-terminal kinase-mediated up-regulation of death receptor 5 contributes to induction of apoptosis by the novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1, 9-dien-28-oate in human lung cancer cells. Cancer Res. 2004 Oct 15;64(20):7570-8. PubMed PMID: 15492284.

48: Honda T, Janosik T, Honda Y, Han J, Liby KT, Williams CR, Couch RD, Anderson AC, Sporn MB, Gribble GW. Design, synthesis, and biological evaluation of biotin conjugates of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid for the isolation of the protein targets. J Med Chem. 2004 Sep 23;47(20):4923-32. PubMed PMID: 15369396.

49: Ikeda T, Sporn M, Honda T, Gribble GW, Kufe D. The novel triterpenoid CDDO and its derivatives induce apoptosis by disruption of intracellular redox balance. Cancer Res. 2003 Sep 1;63(17):5551-8. PubMed PMID: 14500394.

50: Suh WS, Kim YS, Schimmer AD, Kitada S, Minden M, Andreeff M, Suh N, Sporn M, Reed JC. Synthetic triterpenoids activate a pathway for apoptosis in AML cells involving downregulation of FLIP and sensitization to TRAIL. Leukemia. 2003 Nov;17(11):2122-9. PubMed PMID: 12931220.

51: Kim KB, Lotan R, Yue P, Sporn MB, Suh N, Gribble GW, Honda T, Wu GS, Hong WK, Sun SY. Identification of a novel synthetic triterpenoid, methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate, that potently induces caspase-mediated apoptosis in human lung cancer cells. Mol Cancer Ther. 2002 Jan;1(3):177-84. PubMed PMID: 12467212.

52: Konopleva M, Tsao T, Ruvolo P, Stiouf I, Estrov Z, Leysath CE, Zhao S, Harris D, Chang S, Jackson CE, Munsell M, Suh N, Gribble G, Honda T, May WS, Sporn MB, Andreeff M. Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia. Blood. 2002 Jan 1;99(1):326-35. PubMed PMID: 11756188.

53: Wang Y, Porter WW, Suh N, Honda T, Gribble GW, Leesnitzer LM, Plunket KD, Mangelsdorf DJ, Blanchard SG, Willson TM, Sporn MB. A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor gamma. Mol Endocrinol. 2000 Oct;14(10):1550-6. PubMed PMID: 11043571.