Cabozantinib (XL184, BMS-907351)
(Synonyms: 卡博替尼; XL184; BMS-907351) 目录号 : GC15779
A VEGFR2 inhibitor
Cas No.:849217-68-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| 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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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]。
| 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 |
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| % 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.
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Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth
The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling.
Cabozantinib
No information is available on the clinical use of cabozantinib during breastfeeding. Because cabozantinib is more than 97% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life ranges from 55 to 99 hours and it might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during cabozantinib therapy and for 4 months after the last dose.
XL184 (cabozantinib) for medullary thyroid carcinoma
Introduction: Intrathyroidal medullary thyroid carcinoma (MTC) can generally be cured by surgery, but distant metastases are often already present at diagnosis.Currently, there is no effective treatment for metastatic MTC. In these cases, consensus treatment guidelines explicitly recommend new experimental drugs. Several kinase inhibitors are now being tested for treatment of MTC in clinical trials and XL184, an oral, small-molecule multi-kinase inhibitor, seems to be one of the most promising of these compounds.
Areas covered: We review preliminary data on the safety and efficacy of XL184 in metastatic MTC based on an extensive search of the literature, which included published articles, abstracts and website information. In particular,the review focuses on the rationale for using XL184 in advanced MTC. The compound has been specifically designed to target multiple signaling pathways,and this is expected to produce synergistic antitumor effects superior to those achieved by single-kinase inhibition. Preliminary results from the Phase I study of XL184 seem to support this hypothesis.
Expert opinion: Multiple receptor tyrosine kinases (RTKs) are concomitantly activated in the same tumor. The blockade of a single RTK may engage compensatory signaling that maintains cell growth. Targeting multiple kinases might overcome both intrinsic and acquired resistance to antitumoral drugs.
Cabozantinib (XL184) Inhibits Growth and Invasion of Preclinical TNBC Models
Purpose: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that is associated with poor clinical outcome. There is a vital need for effective targeted therapeutics for TNBC patients, yet treatment strategies are challenged by the significant intertumoral heterogeneity within the TNBC subtype and its surrounding microenvironment. Receptor tyrosine kinases (RTK) are highly expressed in several TNBC subtypes and are promising therapeutic targets. In this study, we targeted the MET receptor, which is highly expressed across several TNBC subtypes.
Experimental design: Using the small-molecule inhibitor cabozantinib (XL184), we examined the efficacy of MET inhibition in preclinical models that recapitulate human TNBC and its microenvironment. To analyze the dynamic interactions between TNBC cells and fibroblasts over time, we utilized a 3D model referred to as MAME (Mammary Architecture and Microenvironment Engineering) with quantitative image analysis. To investigate cabozantinib inhibition in vivo, we used a novel xenograft model that expresses human HGF and supports paracrine MET signaling.
Results: 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. Treatment with XL184 had no significant effects on MET(neg) breast cancer cell growth. In vivo assays demonstrated that cabozantinib treatment significantly inhibited TNBC growth and metastasis.
Conclusions: Using preclinical TNBC models that recapitulate the breast tumor microenvironment, we demonstrate that cabozantinib inhibition is an effective therapeutic strategy in several TNBC subtypes.
Targeting the C-MET/HGF Signaling Pathway in Pancreatic Ductal Adenocarcinoma
The c-mesenchymal-epithelial transition factor (c-MET) is involved in the tumorigenesis of various cancers. HGF/Met inhibitors are now attracting considerable interest due to their anti-tumor activity in multiple malignancies such as pancreatic cancer. It is likely that within the next few years, HGF/Met inhibitors will become a crucial component for cancer management. In this review, we summarize the role of HGF/Met pathway in the pathogenesis of pancreatic cancer, with particular emphasize on HGF/Met inhibitors in the clinical setting, including Cabozantinib (XL184, BMS-907351), Crizotinib (PF-02341066), MK-2461, Merestinib (LY2801653), Tivantinib (ARQ197), SU11274, Onartuzumab (MetMab), Emibetuzumab (LY2875358), Ficlatuzumab (AV- 299), Rilotumumab (AMG 102), and NK4 in pancreatic cancer.