Bardoxolone methyl
(Synonyms: 甲基巴多索隆; RTA 402; NSC 713200; CDDO Methyl ester) 目录号 : GC11572
A synthetic triterpenoid with potent anticancer and antidiabetic activity
Cas No.:218600-53-4
Sample solution is provided at 25 µL, 10mM.
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Bardoxolone methyl is an activator of the KEAP1-Nrf2 pathway [1] and also inhibits the pro-inflammatory transcription factor NF-kB [2] which can protect kidneys from aristolochic acid (AA)-induced acute kidney injury (AKI) with IC50 value of 1.5 nM and LC50 value of 2.1 µM [3].
Nrf2, a transcription factor, is a basic leucine zipper (bZIP) protein that regulates the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation [4], such as NADPH, Glutathione, SRXN1, TXNRD1, HMOX1, GST, UGT and Mrps. Nrf2 plays an important role in the maintenance of homeostasis which can control the basal and inducible expression of a battery of genes with diverse physiological roles, including the preservation of redox balance, the metabolism and detoxification of xenobiotics, and the regulation of multiple metabolic pathways that ensure the provision of cellular energy[5].
Bardoxolone methyl is a synthetic oleanane triterpenoid compound, which has no effect on the function and histology of normal kidneys but increased renal expression of Nrf2, HO-1 and NQO1 by western blotting analysis of mice kidneys and immunofluorescence staining, and can prevent AA-induced acute kidney injury and reduce AAI-induced TI injury in mRNA and protein levels through real-time PCR.[6] In conclusion, Bardoxolone methyl can prevent AAI-induced renal damage, and it may exert this renoprotective effects by activating the Nrf2 signaling pathway and inducing the downstream target genes expression. A phase 3 clinical trial evaluating bardoxolone methyl for the treatment of chronic kidney disease (CKD) was terminated in October 2012 after patients treated with the drug were found to have experienced a higher rate of heart-related adverse events, including heart failure, hospitalizations and deaths.[7] Now in 2014, Kyowa Hakko Kirin announced plans to evaluate both safety and efficacy of bardoxolone methyl in a Phase 2 clinical study to be performed in Japan for the treatment of CKD associated with type 2 diabetes.[8]
References:
1.Yates MS, Tauchi M, Katsuoka F, et al."Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes." Mol Cancer Ther 2007, 6 (1): 154–62.
2.Ahamd R, Raina D, Meyer C, et al.. "Triterpenoid CDDO-Me blocks the NF-kappaB pathway by direct inhibition of IKKbeta on Cys-179.". J Biol Chem, 2006, 281 (47): 35764–9.
3.Ian M. Copple. et al. Chemical Tuning Enhances Both Potency Toward Nrf2 and In Vitro Therapeutic Index of Triterpenoids. TOXICOLOGICAL SCIENCES,2014,140(2), 462–469.
4.Gold R, Kappos L. Et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N. Engl. J. Med. 2012, 367 (12): 1098–107.
5.Ma, Q. Role of nrf2 in oxidative stress and toxicity. Annu. Rev. Pharmacol. Toxicol. 2013,53:401–426.
6.Juan Wua. et al. Bardoxolone methyl (BARD) ameliorates aristolochic acid (AA)-induced acute kidney injury through Nrf2 pathway. Toxicology. 2014, 318(6):22–31.
7.de Zeeuw D, Akizawa T, Audhya P, et al. "Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease.". N Engl J Med,2013,369 (26): 2492–503.
8.Kyowa Hakko Kirin Co Ltd announces future development direction for bardoxolone methyl (RTA 402).
| Kinase experiment [1]: | |
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IKK assay |
To determine the effect of CDDO-Me on TNF-induced IKK activation, IKK was analyzed. Briefly, the IKK complex from whole-cell extracts was precipitated with antibody against IKKα and IKKβ and then treated with protein A/G-Sepharose beads. After 2 hrs, the beads were washed with lysis buffer and then resuspended in a kinase assay mixture containing 50 mmol/L HEPES (pH 7.4), 20 mmol/L MgCl2, 2 mmol/L DTT, 20 μCi [γ-32P]ATP, 10 μmol/L unlabeled ATP, and 2 μg of substrate glutathione S-transferase-IκBα (amino acids 1 ~ 54). After incubation at 30°C for 30 mins, the reaction was terminated by boiling with SDS sample buffer for 5 mins. Finally, the protein was resolved on 10% SDS-PAGE, the gel was dried, and the radioactive bands were visualized with a Storm820. To determine the total amounts of IKK-α and IKK-β in each sample, 50 μg of whole-cell proteins were resolved on 7.5% SDS-PAGE, electrotransferred to a nitrocellulose membrane, and then blotted with either anti-IKK-α or anti-IKK-β antibody. |
| Cell experiment [2]: | |
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Cell lines |
HL-60, KG-1 and NB4 cells |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
|
Reaction Conditions |
~ 5 μM; 72 hrs |
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Applications |
In leukemia cells, such as HL-60, KG-1, and NB4 cells, Bardoxolone Methyl decreased cell viability with the IC50 values of 0.4, 0.4 and 0.27 μM, respectively. |
| Animal experiment [3]: | |
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Animal models |
Female A/J mice i.p. injected with vinyl carbamate |
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Dosage form |
60 or 400 mg/kg; p.o.; the mice fed Bardoxolone Methyl for 2 weeks and then switched to a week of control diet, for 15 weeks. |
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Applications |
At the dose of 60 mg, Bardoxolone Methyl reduced the number, size, as well as severity of lung tumors in vivo. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. 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. [2]. 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. [3]. 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. |
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| Cas No. | 218600-53-4 | SDF | |
| 别名 | 甲基巴多索隆; RTA 402; NSC 713200; CDDO Methyl ester | ||
| 化学名 | methyl (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-carboxylate | ||
| Canonical SMILES | CC1(CCC2(CCC3(C(C2C1)C(=O)C=C4C3(CCC5C4(C=C(C(=O)C5(C)C)C#N)C)C)C)C(=O)OC)C | ||
| 分子式 | C32H43NO4 | 分子量 | 505.69 |
| 溶解度 | ≥ 25.3 mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9775 mL | 9.8875 mL | 19.775 mL |
| 5 mM | 0.3955 mL | 1.9775 mL | 3.955 mL |
| 10 mM | 0.1977 mL | 0.9887 mL | 1.9775 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet