Novel synthetic triterpenoid, bardoxolone methyl, is an antioxidant inflammation modulator that potently induces Nrf2 and inhibits Janus-activated kinase/STAT signaling, NF-κB. It has been demonstrated that bardoxolone methyl causes cancer cell lines to differentiate, stop growing, and undergo apoptosis[2].

Although the groups' mRNA expression is similar, kidney sections from the bardoxolone methyl-treated monkeys show reduced megalin protein expression. Densitometry analyses validate the observed reduction in megalin protein expression, revealing a significant decrease in megalin protein expression in the monkey kidney upon administration of Bardoxolone methyl. Both the mRNA and protein expression of cubilin in the kidney are unaffected by the administration of bardoxolone methyl. On day 28, the creatinine clearance of monkeys given Bardoxolone methyl was considerably different from that of baseline and animals given a vehicle treatment. Urinary albumin-to-creatinine ratios (UACRs), as measured from 24-hour urine collections, are significantly higher after 28 days of Bardoxolone methyl administration in comparison to animals receiving vehicle. Notably, UACRs rose by 27.9% in monkeys treated with bardoxolone methyl and decreased by 53.3% in animals treated with a vehicle[3]. For 21 weeks, male C57BL/6J mice are either fed a low-fat diet (LFD), only a high-fat diet (HFD), or oral BARD during HFD feeding (HFD/BARD). HFD mice show a significant increase in F4/80 crown-like structures (+95%; p<0.001) in comparison to LFD mice, which is effectively prevented by BARD (−50%; p<0.01). Similarly, compared to LFD mice and HFD/BARD mice, the number of F4/80 interstitial macrophages in HFD mice is significantly higher by 98% (p<0.001) and 32% (p<0.01), respectively[4].

[1]. McCullough PA, et al. Cardiac and renal function in patients with type 2 diabetes who have chronic kidney disease: potential effectsof bardoxolone methyl. Drug Des Devel Ther. 2012;6:141-9.
[2]. Hong DS, et al. A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas. Clin Cancer Res. 2012 Jun 15;18(12):3396-406.
[3]. Reisman SA, et al. Bardoxolone Methyl Decreases Megalin and Activates Nrf2 in the Kidney. J Am Soc Nephrol. 2012 Oct;23(10):1663-73.
[4]. Dinh CH, et al. Bardoxolone Methyl Prevents Mesenteric Fat Deposition and Inflammation in High-Fat Diet Mice. ScientificWorldJournal. 2015;2015:549352

Bardoxolone is a member of cyclohexenones.
Bardoxolone has been used in trials studying the treatment of LYMPHOMA and Solid Tumors. It is a synthetic triterpenoid and a highly potent activator of redox-sensitive signaling pathways that induce programmed cell death (apoptosis) in cancer cells that are under high levels of intrinsic oxidative stress. In contrast, Bardoxolone in normal cells induces protective antioxidant/anti-inflammatory responses.
Bardoxolone is a synthetic triterpenoid compound with potential antineoplastic and anti-inflammatory activities. Bardoxolone blocks the synthesis of inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2), two enzymes involved in inflammation and carcinogenesis. This agent also inhibits the interleukin-1 (IL-1)-induced expression of the pro-inflammatory proteins matrix metalloproteinase-1 (MMP-1) and matrix metalloproteinase-13 (MMP-13) and the expression of Bcl-3; Bcl-3 is an IL-1-responsive gene that preferentially contributes to MMP-1 gene expression.

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Mechanism of Action
Bardoxolone, a synthetic triterpenoid, is a highly potent activator of redox-sensitive signaling pathways that induce programmed cell death (apoptosis) in cancer cells that are under high levels of intrinsic oxidative stress. In contrast, Bardoxolone in normal cells induces protective antioxidant/anti-inflammatory responses. Intensive research in animal models of human cancer has demonstrated that Bardoxolone is a potent anticancer agent with a well-characterized ability to inhibit growth and cause regression of tumors as a single agent and in combination with radiation and chemotherapy. Bardoxolone also suppresses radiation- and chemotherapy-induced damage (e.g., oral mucositis) in normal tissues at dose levels that also produce an anti-cancer effect. Bardoxolone induces apoptosis through both caspase-independent and -dependent mechanisms, the latter involving caspase-8 activation, Bid cleavage, cytochrome c release, and caspase-3 activation. Furthermore, JNK, p38, and ERK pathways are involved in Bardoxolone-induced apoptosis of tumor cell lines mediated by disrupted intracellular redox balance and involving decreased glutathione and increased reactive oxygen species. Study shows that Bardoxolone enhances p42 CEBPA protein at the level of translation.

C31H41NO4

491.672

491.303

218600-44-3

400010

White to yellow solid powder

1.2±0.1 g/cm3

632.9±55.0 °C at 760 mmHg

336.6±31.5 °C

0.0±4.0 mmHg at 25°C

1.575

5.76

1

5

1

36

1200

7

C[C@@]12CC[C@]3(CCC(C[C@H]3[C@H]1C(=O)C=C4[C@]2(CC[C@@H]5[C@@]4(C=C(C(=O)C5(C)C)C#N)C)C)(C)C)C(=O)O

TXGZJQLMVSIZEI-UQMAOPSPSA-N

InChI=1S/C31H41NO4/c1-26(2)10-12-31(25(35)36)13-11-30(7)23(19(31)16-26)20(33)14-22-28(5)15-18(17-32)24(34)27(3,4)21(28)8-9-29(22,30)6/h14-15,19,21,23H,8-13,16H2,1-7H3,(H,35,36)/t19-,21-,23-,28-,29+,30+,31-/m0/s1

(4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,7,8,8a,14a,14b-decahydropicene-4a-carboxylic acid

BardoxoloneCDDO RTA-401 RTA 401RTA401

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~203.39 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.08 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.08 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)