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Cabozantinib (XL184, BMS-907351)

现货
Catalog No.
A2977
VEGFR2/Met/Ret/Kit/FLT/AXL抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 750.00
现货
5mg
¥ 700.00
现货
25mg
¥ 2,000.00
现货
100mg
¥ 6,800.00
现货

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Background

Cabozantinib (also called XL184, BMS-907351 Cometriq [1]), is an inhibitor of multiple receptor tyrosine kinases (RTKs), including vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (MET), and rearranged during transfection (RET) [2] [3], with IC50 values of 0.035 nmol/L, 1.3 nmol/L and 5.2 nmol/L to VEGFR2, MET and RET, respectively [4].

RTKs transmit a wide array of extracellular signals for regulating differentiation and proliferation to cells. Ligand binding triggers many events such as autophosphorylation of tyrosine residues and receptor dimerization [5].

TT cell line was a human MTC cell line that had an activating C634W RET mutant and was expressing calcitonin. In this cell line, cabozantinib inhibited the autophosphorylation of RET with an IC50 value of 85 nmol/L. In TT cells grown for 72 h in 10% serum, cabozantinib dose-dependently inhibited cell proliferation with an IC50 value of 94 nmol/L [4].

Administrated with cabozantinib daily orally at doses of 10, 30, or 60 mg/kg, nu/nu mice bearing TT xenograft tumors, showed a significantly inhibited tumor growth compared with vehicle-treated group. At both doses of 30 and 60 mg/kg, cabozantinib caused markedly and significantly reduced circulating calcitonin (75%; p< 0.005) in serum compared with vehicle-treated control animals [4].

References:
[1].  Michael G. Doran, Daniel E. Spratt, John Wongvipat, et al. Cabozantinib Resolves Bone Scans in Tumor-Naїve Mice Harboring Skeletal Injuries. Molecular Imaging, 2014, 13:1-5.
[2].  Rossella Elisei, Martin J. Schlumberger, Stefan P. Müller, et al. Cabozantinib in Progressive Medullary Thyroid Cancer. J. Clin. Oncol., 2013, 31(29):3639-46.
[3].  Razelle Kurzrock, Steven I. Sherman, Douglas W. Ball, et al. Activity of XL184 (Cabozantinib), an Oral Tyrosine Kinase Inhibitor, in Patients with Medullary Thyroid Cancer. J. Clin. Oncol., 2011, 29(19):2660-6.
[4].  Frauke Bentzien, Marcus Zuzow, Nathan Heald, et al. In Vitro and In Vivo Activity of Cabozantinib (XL184), an Inhibitor of RET, MET, and VEGFR2, in a Model of Medullary Thyroid Cancer. Thyroid, 2013, 23(12):1569-1577.
[5].  Xianhua Piao, Robert Paulson, Peter van der Geer, et al. Oncogenic mutation in the Kit receptor tyrosine kinase alters substrate specificity and induces degradation of the protein tyrosine phosphatase SHP-1. Proc. Natl. Acad. Sci. USA., 1996, 93(25):14665-14669.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt501.51
Cas No.849217-68-1
FormulaC28H24FN3O5
Solubility≥25.1mg/mL in DMSO
Chemical Name1-N-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
SDFDownload SDF
Canonical SMILESCOC1=CC2=C(C=CN=C2C=C1OC)OC3=CC=C(C=C3)NC(=O)C4(CC4)C(=O)NC5=CC=C(C=C5)F
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

细胞实验[1]:

细胞系

人类微血管内皮细胞(HMVEC)

溶解方法

该化合物在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

IC50: 6.7 nM,7天

实验结果

在cabozantinib存在的情况下,使用VEGF孵育HMVEC细胞,针对CD31的免疫染色可以观察到小管形成。Cabozantinib抑制小管形成,IC50值为6.7 nM,目前没有证据表明该药物有细胞毒性,这表明cabozantinib具有抗血管生成作用而没有细胞毒性。

动物实验[1]:

动物模型

植入H441细胞的雌性nu/nu小鼠

剂量

口服给药,100 mg/kg,8 hours

实验结果

在具有组成性磷酸化MET的H441肿瘤中,口服单一剂量100mg/kg的cabozantinib,给药2至8小时后,MET的磷酸化被抑制,治疗后48小时,MET磷酸化恢复到基础水平,说明药物效果是可逆的。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

[1] Yakes F M, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Molecular cancer therapeutics, 2011, 10(12): 2298-2308.

生物活性

Description Cabozantinib (XL184, BMS-907351)是一种有效的VEGFR2抑制剂,IC50值为0.035 nM,也抑制c-Met、Ret、Kit、Flt-1/3/4、Tie2和AXL,IC50值为1.3 nM、4 nM、4.6 nM、12 nM/11.3 nM/6 nM、14.3 nM和7 nM。
靶点 VEGFR2 c-Met Ret c-Kit Flt-1/3/4 Tie2
IC50 0.035 nM 1.3 nM 4 nM 4.6 nM 12 nM/11.3 nM/6 nM 14.3 nM

质量控制

化学结构

Cabozantinib (XL184, BMS-907351)

相关生物数据

Cabozantinib (XL184, BMS-907351)

相关生物数据

Cabozantinib (XL184, BMS-907351)