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Bardoxolone methyl

现货
Catalog No.
A3221
IKK抑制剂,强效的抗氧化炎性反应调节剂。
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 650.00
现货
50mg
¥ 1,640.00
现货
500mg
¥ 6,570.00
Ship with 10-15 days

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Background

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).

Chemical Properties

StorageStore at -20°C
M.Wt505.69
Cas No.218600-53-4
FormulaC32H43NO4
SynonymsNSC 713200; RTA 402; CDDO Methyl ester
Solubility≥25.3 mg/mL in DMSO, <2.15 mg/mL in EtOH, <2.52 mg/mL in H2O
Chemical Namemethyl (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
SDFDownload SDF
Canonical SMILESCC1(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
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验 [1]:

IKK试验

对IKK进行分析,以确定CDDO-ME对TNF诱导的IKK活化的作用。在全细胞提取物中,使用IKKα和IKKβ抗体将IKK复合物沉淀,再用蛋白A/G-琼脂糖珠进行处理。2小时后,使用裂解缓冲液清洗珠粒,然后将其重悬于含有50 mmol/L HEPES (pH 7.4),20 mmol/L MgCl2,2 mmol/L DTT, 20 μCi [γ-32P]ATP,10 μmol/L未标记的ATP以及2 μg谷胱甘肽S-转移酶-IκBα底物(氨基酸1 ~ 54)的激酶测定混合物中。在30℃下,将其孵育30分钟,然后加入SDS样品缓冲液,沸浴5分钟终止上述反应。最后,使用10% SDS-PAGE分离蛋白,凝胶干燥后,使用Storm820显示放射性条带。为了测定每个样品中的IKK-α和IKK-β总量,采用7.5% SDS-PAGE分离50 μg全细胞蛋白,通过电转移将蛋白转移至硝酸纤维素膜上,然后使其与IKKα和IKKβ抗体进行印迹杂交。

细胞实验 [2]:

细胞系

HL-60、KG-1和NB4细胞

制备方法

在DMSO中的溶解度大于10 mM。若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月。

反应条件

~ 5 μM;72小时

实验结果

在白血病细胞中,如HL-60、KG-1和NB4细胞,Bardoxolone Methyl降低细胞活力,其IC50值分别为0.4、0.4和0.27 μM。

动物实验 [3]:

动物模型

腹腔注射乙烯基氨基甲酸酯的雌性A/J小鼠

给药剂量

60或400 mg/kg;口服给药;给予小鼠Bardoxolone Methyl,持续2周,再给予小鼠正常饮食,持续1周,上述过程持续15周。

实验结果

在剂量为60 mg时,Bardoxolone Methyl在体外减少肺肿瘤的数量、大小以及严重性。

其它注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

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.

生物活性

Description Bardoxolone methyl是一种可口服的抗氧化炎性反应调节剂。
靶点 antioxidant inflammation          
IC50            

质量控制

化学结构

Bardoxolone methyl