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BEZ235 Tosylate

现货
Catalog No.
A3238
MTOR/ PI3K抑制剂
组合的产品项目
规格价格库存 数量
100mg
¥ 880.00
Ship with 10-15 days
500mg
¥ 2,800.00
Ship with 10-15 days

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Background

BEZ235 is an imidazoquinoline derivative inhibiting both PI3K and mTOR kinases with low nanomolar IC50s. It was well tolerated in preclinical animal studies as well as in clinical trials with manageable gastrointestinal side-effects[1, 2]. It competes with ATP by binding to the ATP-binding site of kinases and reversibly reduces enzyme activity, resulting in growth arrest of tumor cells in G1 phase[1]. Besides the inhibition of cell growth, BEZ235 blocks VEGF-induced angiogenesis[3]. It may also inhibit DNA-PKcs[4].

BEZ235 has shown potential anti-tumor activity both in vitro and in vivo. It inhibited growth of multiple cancer cell lines independently of mutation status in PI3K pathway[5]. In xenograft mice models, it blocked PI3K signaling and showed antitumor activity[1, 5]. Combination study demonstrated that it enhances the efficacy of temozolomide[1].

Clinical data shows anti-tumor activity of BEZ235 treatment, especially in cancer patients with deregulated PI3K signaling pathway. This compound is currently under investigation in multiple clinical trials either as monotherapy or in combination with other agents.

References:
1. Maira SM, Stauffer F, Brueggen J et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 2008; 7: 1851-1863.
2. Markman B, Tabernero J, Krop I et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann Oncol 2012; 23: 2399-2408.
3. Schnell CR, Stauffer F, Allegrini PR et al. Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. Cancer Res 2008; 68: 6598-6607.
4. Mukherjee B, Tomimatsu N, Amancherla K et al. The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKCs-mediated DNA damage responses. Neoplasia 2012; 14: 34-43.
5. Serra V, Markman B, Scaltriti M et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 2008; 68: 8022-8030.

文献引用

1. Winter PS, et al. "RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis." Sci Signal. 2014 Dec 23. PMID:25538080

Chemical Properties

StorageStore at -20°C
M.Wt641.74
Cas No.1028385-32-1
FormulaC37H31N5O4S
SynonymsNVP-BEZ 235 Tosylate; BEZ-235 Tosylate
SolubilitySoluble in DMSO
Chemical Name4-methylbenzenesulfonic acid;2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-ylimidazo[4,5-c]quinolin-1-yl)phenyl]propanenitrile
SDFDownload SDF
Canonical SMILESCC1=CC=C(C=C1)S(=O)(=O)O.CC(C)(C#N)C1=CC=C(C=C1)N2C3=C4C=C(C=CC4=NC=C3N(C2=O)C)C5=CC6=CC=CC=C6N=C5
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]:

蛋白激酶实验

除了不含最后20个氨基酸的α之外,PI3Kα、β和δ蛋白由p85 NH2末端的iSH2结构域融合到全长p110蛋白。PI3Kγ为缺失前144个氨基酸的全长蛋白质将所有构建体融合至COOH末端His标签以便于纯化,然后克隆到pBlue-Bac4.5(α、β和δ亚型)或pVL1393(γ亚型)质粒。然后将不同载体与BaculoGold WT基因组DNA共转染。使用Kinase-Glo测定法测试化合物对PI3K的活性。激酶反应在384孔黑板(Corning)中进行。每孔加入50 μL实验项目(90%DMSO)和5μL反应缓冲液,反应缓冲液包含10 mmol/L Tris-HCl (pH 7.5)、50 mmol/L NaCl、3 mmol/L MgCl2、1 mmol/L DTT和0.05% CHAPS,还包含有10 μg/mL PI底物(1-α-磷脂酰肌醇)和Avanti Polar Lipids,在3%辛基葡糖苷中制备。加入PI3K蛋白,110α、p110β、p110δ和p110γ的含量分别为10、25、10和150 nmol/L。通过在反应缓冲液加入5μL浓度为1 μmol/L的ATP开始反应,p110α、p110β和p110δ反应60分钟,p110γ反应120分钟,然后通过加入10 μL激酶-Glo缓冲液。然后在Synergy 2读取器(BioTek)读取板中进行发光检测。

细胞实验 [1]:

细胞系

人前列腺肿瘤细胞系PC3M,U87MG胶质母细胞瘤细胞系

溶解方法

可溶于DMSO。若获取更高浓度的溶液,可在37℃下孵育10分钟,随后在超声波浴中摇匀。-20℃以下可储存数月。

反应条件

10-50 nmol/L,30 min

应用

在U87MG胶质母细胞瘤PTEN阴性细胞系中,NVP-BEZ235以剂量依赖性方式降低S473P-Akt和T308P-Akt水平。在稳定表达GFP-FKHRL1嵌合蛋白的U2OS细胞中,NVP-BEZ235诱发核重新定位。在PTEN无效细胞系PC3M和U87MG中,NVP-BEZ235以剂量依赖性方式降低细胞增殖,平均GI50为10-12 nmol/L。在PC3M细胞中,NVP-BEZ235(10-50 nmol/L)增加了G1群体细胞数目。在p53阴性PC3M细胞系中,NVP-BEZ235显著增加细胞周期蛋白依赖性激酶抑制剂p27Kip1的量。

动物实验 [1]:

动物模型

PC3M肿瘤裸鼠,U87MG荷瘤小鼠

给药剂量

口服,每日50 mg/kg或25 mg/kg每日两次

应用

NVP-BEZ235(50 mg/kg)在血浆中迅速出现,0.5h的Cmax为1.68 μmol/L,C24h为0.03 μmol/L。在U87MG荷瘤小鼠中,NVP-BEZ235的次优剂量(25 mg/kg/d)至最佳(45 mg/kg/d)引起肿瘤消退。NVP-BEZ235作为单一药物口服时引起疾病停滞,体内组合研究表明NVP-BEZ235可以增强其它抗癌剂的功效。

注意事项

由于实验环境的不同,实际溶解度可能与理论值略有不同,请测试室内所有化合物的溶解度。

References:

[1]. Maira S M, Stauffer F, Brueggen J, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity[J]. Molecular cancer therapeutics, 2008, 7(7): 1851-1863

质量控制

化学结构

BEZ235 Tosylate

相关生物数据

BEZ235 Tosylate

相关生物数据

BEZ235 Tosylate