Cabozantinib (XL184, BMS-907351)
(Synonyms: 卡博替尼; XL184; BMS-907351) 目录号 : GC15779
Cabozantinib (XL184,BMS-907351) 是一种新型 MET 和 VEGFR2 抑制剂，可同时抑制转移、血管生成和肿瘤生长。
Cas No.:849217-68-1
Sample solution is provided at 25 µL, 10mM.
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Cabozantinib (XL184,BMS-907351) is a novel MET and VEGFR2 inhibitor that simultaneously inhibits metastasis, angiogenesis and tumor growth[1]. Its IC50 values for VEGFR2 and c-Met are 0.035 nM and 1.3 nM[2].
Cabozantinib(XL184) treatment of MAME cultures of MDA-MB-231 and HCC70 cells (HGF-expressing fibroblasts) was cytotoxic and significantly reduced multicellular invasive outgrowths, even in cultures with HGF-expressing fibroblasts[3]. The cellular stress induced by Cabozantinib resulted in the induction of ICD (a peculiar type of apoptosis) in DU-145 cell line[4]. Cabozantinib has been reported to inhibit MMP-1 expression by blocking the HGF-MET signaling pathway in bladder cancer cells[5]. MMP-1 was significantly decreased in ESCC cells treated with cabozantinib, which was the reason for the decreased migration activity of ESCC cells treated with cabozantinib[6].
Cabozantinib inhibits tumor growth in a dose-dependent manner in human tumor models in rodents[1]. In vivo pharmacodynamic studies showed substantial inhibition of RET in TT xenograft tumors following a single oral dose of cabozantinib[7]. Cabozantinib showed excellent antitumor effects in vivo using CRC(colorectal cancer) explants model[8].
References:
[1]. Yakes F Michael,Chen Jason, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth.[J]. Molecular cancer therapeutics,2011,10(12).
[2]. Weon-Kyoo You, Barbara Sennino, et al. VEGF and c-Met Blockade Amplify Angiogenesis Inhibition in Pancreatic Islet Cancer[J]. Microenvironment and Immunology,2011.
[3]. Sameni Mansoureh,Tovar Elizabeth A, et al. Cabozantinib (XL184) Inhibits Growth and Invasion of Preclinical TNBC Models.[J]. Clinical cancer research : an official journal of the American Association for Cancer Research,2016,22(4).
[4] Scirocchi Fabio,Napoletano Chiara,et al. Immunogenic Cell Death and Immunomodulatory Effects of Cabozantinib[J]. Frontiers in Oncology,2021,11.
[5] Shintani T, Kusuhara Y, et al. The involvement of hepatocyte growth factor-MET-matrix metalloproteinase 1 signaling in bladder cancer invasiveness and proliferation. Effect of the MET inhibitor, cabozantinib (XL184), on bladder cancer cells. Urology. (2017) 101:169.e7-13. doi: 10.1016/j.urology.2016.12.006.
[6] Pei-Wen Yang, Yu-Cheng Liu, et al. Cabozantinib (XL184) and R428 (BGB324) Inhibit the Growth of Esophageal Squamous Cell Carcinoma (ESCC)[J]. Frontiers in Oncology, 2019.
[7] Bentzien Frauke,Zuzow Marcus, 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.[J]. Thyroid : official journal of the American Thyroid Association,2013,23(12).
[8] Scott Aaron J,Arcaroli John J,et al. Cabozantinib Exhibits Potent Antitumor Activity in Colorectal Cancer Patient-Derived Tumor Xenograft Models via Autophagy and Signaling Mechanisms.[J]. Molecular cancer therapeutics,2018,17(10).
Cabozantinib (XL184,BMS-907351) 是一种新型 MET 和 VEGFR2 抑制剂,可同时抑制转移、血管生成和肿瘤生长[1]。其对 VEGFR2 和 c-Met 的 IC50 值分别为 0.035 nM 和 1.3 nM[2]。
Cabozantinib(XL184) 处理 MDA-MB-231 和 HCC70 细胞的 MAME 培养物（表达 HGF 的成纤维细胞）具有细胞毒性并显着减少多细胞侵袭性生长,即使在含有表达 HGF 的成纤维细胞的培养物中也是如此[3]。 Cabozantinib 诱导的细胞应激导致 DU-145 细胞系发生 ICD（一种特殊类型的细胞凋亡）[4]。据报道,卡博替尼可通过阻断膀胱癌细胞中的 HGF-MET 信号通路来抑制 MMP-1 的表达[5]。卡博替尼处理后ESCC细胞MMP-1显着降低,这是卡博替尼处理后ESCC细胞迁移活性降低的原因[6]。
卡博替尼抑制肿瘤生长在啮齿动物的人类肿瘤模型中呈剂量依赖性[1]。体内药效学研究表明,单次口服卡博替尼[7]后,TT 异种移植肿瘤中的 RET 得到显着抑制。使用 CRC（结直肠癌）外植体模型,卡博替尼在体内表现出优异的抗肿瘤作用[8]。
| Cell experiment [1]: | |
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Cell lines |
DU-145 cell lines |
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Preparation Method |
DU145 cells were labeled with carboxyfluorescein succinimidyl ester (CFSE) (1µM) and incubated for 20 min at 37°C protecting from light. After two washes in PBS (37°C), the cells were treated with 2.5 mg/ml of Cabozantinib(XL184). |
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Reaction Conditions |
2.5 mg/ml, 48h |
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Applications |
DU-145 cell lines expressed MET, and Cabozantinib(XL184) treatment had a cytostatic effect, blocking cells in G1 phase. Cabozantinib(XL184) induced an inhibition of the autophagic pathway in DU-145 cells, through an upregulation of the mTOR complex. This may be related to the high expression of the AXL that is observed in DU-145; this is also an RTK target for Cabozantinib(XL184). |
| Animal experiment [2]: | |
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Animal models |
6- to 8-week-old NOD-SCID male mice |
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Dosage form |
30 mg/kg/day, oral gavage |
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Applications |
The expression of matrix metalloproteinase-1 (MMP-1), a crucial factor in cell migration, was markedly decreased in the cabozantinib(XL 184)-treated mice compared to in the vehicle group (P |
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References: [1].Scirocchi Fabio,Napoletano Chiara,et al. Immunogenic Cell Death and Immunomodulatory Effects of Cabozantinib[J]. Frontiers in Oncology,2021,11. |
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| Cas No. | 849217-68-1 | SDF | |
| 别名 | 卡博替尼; XL184; BMS-907351 | ||
| 化学名 | 1-N-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide | ||
| Canonical SMILES | COC1=CC2=C(C=CN=C2C=C1OC)OC3=CC=C(C=C3)NC(=O)C4(CC4)C(=O)NC5=CC=C(C=C5)F | ||
| 分子式 | C28H24FN3O5 | 分子量 | 501.51 |
| 溶解度 | ≥ 25.1mg/mL in DMSO | 储存条件 | 4°C, protect from light |
| 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 | 1.994 mL | 9.9699 mL | 19.9398 mL |
| 5 mM | 0.3988 mL | 1.994 mL | 3.988 mL |
| 10 mM | 0.1994 mL | 0.997 mL | 1.994 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。
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