1. Protein Tyrosine Kinase/RTK
  2. VEGFR
    c-Met/HGFR
    c-Kit
    TAM Receptor
    FLT3

Cabozantinib (Synonyms: XL184; BMS-907351)

Cat. No.: HY-13016 Purity: 99.92%
Data Sheet SDS Handling Instructions

Cabozantinib is a potent multiple RTKs inhibitor that inhibits VEGFR2, c-Met, Kit, Axl and Flt3 with IC50 of 0.035, 1.3, 4.6, 7 and 11.3 nM, respectively.

For research use only. We do not sell to patients.
Cabozantinib Chemical Structure

Cabozantinib Chemical Structure

CAS No. : 849217-68-1

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10 mM * 1 mL in DMSO $66 In-stock
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10 mg $75 In-stock
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100 mg $145 In-stock
200 mg $245 In-stock
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Other Forms of Cabozantinib:

    Cabozantinib purchased from MCE. Usage Cited in: PLoS One. 2017 Sep 25;12(9):e0185321.

    Treatment with Cabozantinib results in complete inhibition of the c-MET phosphorylation stimulated by HGF at nanomolar concentrations.

    Cabozantinib purchased from MCE. Usage Cited in: J Med Chem. 2016 Jan 14;59(1):358-73.

    Autophosphorylation of RET and its downstream signaling are blocked by 6i. The effect of 6i on autophosphorylation of RET in (A) RET-WT Ba/F3, (B) RET-S891A Ba/F3, (C) RET-V804L Ba/F3 and (D) RET-V804M Ba/F3. (A-D) Ba/F3 cells, stably transformed with the indicated constructs, are treated for 1 h with gradually increasing concentrations of 7a, Cabozantinib and 6i (0-10 μM) and then lysed. Protein extracts are immunoblotted with antibodies specific for the Y905 and Y1062 phosphorylated forms of R

    Cabozantinib purchased from MCE. Usage Cited in: J Med Chem. 2016 Jan 14;59(1):358-73.

    Autophosphorylation of RET and its downstream signaling are blocked by 6i. The effect of 6i on autophosphorylation of RET in (A) RET-WT Ba/F3, (B) RET-S891A Ba/F3, (C) RET-V804L Ba/F3 and (D) RET-V804M Ba/F3. (A-D) Ba/F3 cells, stably transformed with the indicated constructs, are treated for 1 h with gradually increasing concentrations of 7a, Cabozantinib and 6i (0-10 μM) and then lysed. Protein extracts are immunoblotted with antibodies specific for the Y905 and Y1062 phosphorylated forms of R
    • Biological Activity

    • Protocol

    • Technical Information

    • Purity & Documentation

    • References

    Description

    Cabozantinib is a potent multiple RTKs inhibitor that inhibits VEGFR2, c-Met, Kit, Axl and Flt3 with IC50 of 0.035, 1.3, 4.6, 7 and 11.3 nM, respectively.

    IC50 & Target

    IC50: 0.035 nM (VEGFR2), 1.3 nM (c-Met), 4.6 nM (Kit), 7 nM (Axl), 11.3 nM (Flt3)[1]

    In Vitro

    Cabozantinib is a potent inhibitor of MET and VEGFR2 with IC50 values of 1.3 and 0.035 nM, respectively. MET-activating kinase domain mutations Y1248H, D1246N, or K1262R are also inhibited by Cabozantinib (IC50=3.8, 11.8, and 14.6 nM, respectively). Cabozantinib displays strong inhibition of several kinases that have also been implicated in tumor pathobiology, including KIT, RET, AXL, TIE2, and FLT3 (IC50=4.6, 5.2, 7, 14.3, and 11.3 nM, respectively). In cellular assays, Cabozantinib inhibits phosphorylation of MET and VEGFR2, as well as KIT, FLT3, and AXL with IC50 values of 7.8, 1.9, 5.0, 7.5, and 42 μM, respectively. The effect of Cabozantinib on proliferation is evaluated in a number of human tumor cell lines. SNU-5 and Hs746T cells harboring amplified MET are the most sensitive to Cabozantinib (IC50=19 and 9.9 nM, respectively); however, SNU-1 and SNU-16 cells lacking MET amplification are more resistant (IC50=5,223 and 1,149 nM, respectively). MDA-MB-231 and U87MG cells exhibit comparable levels of sensitivity to Cabozantinib (IC50=6,421 and 1,851 nM, respectively), whereas H441, H69, and PC3 cell lines are the least sensitive to Cabozantinib with IC50 values of 21,700, 20,200, and 10,800 nM, respectively. In addition, BaF3 cells expressing human FLT3-ITD, an activating mutation in acute myelogenous leukemia, are sensitive to Cabozantinib (IC50=15 nM) when compared with wild-type BaF3 cells (IC50=9,641 nM)[2].

    In Vivo

    Tumor vascularity decreases after Cabozantinib (XL184), with reductions ranging from 67% at 3 mg/kg to 83% at 30 mg/kg for 7 days[1]. In mouse models, Cabozantinib dramatically alters 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 does 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. On a body weight dosage basis, Cabozantinib plasma exposures range from 6- to 10-fold higher in rats than in mice, which accounts for lower doses inducing tumor growth inhibition/regression in rats than in mice. Subchronic administration of Cabozantinib is well tolerated in mice and rats with no signs of toxicity, as determined by stable and/or increasing body weights during the treatment period[2].

    Clinical Trial
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    References
    Preparing Stock Solutions
    Concentration Volume Mass 1 mg 5 mg 10 mg
    1 mM 1.9940 mL 9.9699 mL 19.9398 mL
    5 mM 0.3988 mL 1.9940 mL 3.9880 mL
    10 mM 0.1994 mL 0.9970 mL 1.9940 mL
    Please refer to the solubility information to select the appropriate solvent.
    Kinase Assay
    [2]

    The inhibition profile of Cabozantinib against a broad panel of 270 human kinases is determined using luciferase-coupled chemiluminescence, 33P-phosphoryl transfer, or AlphaScreen technology. Recombinant human full-length, glutathione S-transferase tag, or histidine tag fusion proteins are used, and IC50 values are determined by measuring phosphorylation of peptide substrate poly(Glu, Tyr) at ATP concentrations at or below the Km for each respective kinase. The mechanism of kinase inhibition is evaluated using the AlphaScreen Assay by determining the IC50 values over a range of ATP concentrations[2]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Cell Assay
    [2]

    Cabozantinib is prepared in DMSO (10 mM) and serially diluted in the appropriate assay media[2].

    The effect of Cabozantinib on proliferation is evaluated in a number of human tumor cell lines, including SNU-5 and Hs746T cells harboring amplified MET, SNU-1 and SNU-16 cells, MDA-MB-231 and U87MG cells, H441, H69, and PC3 cell lines, and BaF3 cells. Cells are seeded in triplicate overnight in media containing 10% FBS. The next day, cells are treated with serial dilutions of Cabozantinib for 48 hours, followed by analysis of proliferation using Cell Proliferation ELISA, BrdUrd[2]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Animal Administration
    [1][2]

    Cabozantinib (XL184) is suspended at a concentration of 5 mg/mL in sterile saline or water (Mice)[1].
    Cabozantinib is formulated in sterile saline/10 mM HCl or in water (Mice)[2].
    Cabozantinib is formulated in sterile saline/10 mM HCl or in water (Rat)[2].

    Mice[1]
    RIP-Tag2 mice in a C57BL/6 background are used as the tumor model. RIP-Tag2 mice are 10 weeks old at the onset of treatment unless otherwise indicated. Cabozantinib is suspended at a concentration of 5 mg/mL in sterile saline or water and administered by gavage daily for 7 days. Dose-dependent effects are studied in mice treated by gavage daily for 7 days: XL880 (1, 10, 20, 40 or 60 mg/kg), Cabozantinib (3, 10, 30, 40 or 60 mg/kg), or XL999 (25, 40, 50, 60 or 75 mg/kg). The time course of effects is studied in mice treated with XL880 (40 mg/kg) for 6 hr, 1, 4, 7 or 14 days. Effects of withdrawal are studied in mice treated with XL880 (40 mg/kg) for 7 days followed by no treatment for 0, 2, 7 or 14 days. Each group contain 4-6 mice.
    Mice[2]
    Female nu/nu mice are used. H441 cells (3×106) are implanted intradermally into the hind flank and when tumors reach approximately 150 mg, tumor weight is calculated using the formula: (tumor volume=length (mm)×width2(mm2)]/2, mice are randomized (n=5 per group) and orally administered a single 100 mg/kg dose of Cabozantinib or vehicle. Tumors are collected at the indicated time points. Pooled tumor lysates are subjected to immunoprecipitation with anti-MET and Western blotting with anti-phosphotyrosine MET. After blot stripping, total MET is quantitated as a loading control.
    Rat[2]
    On day 0 in female Wistar rats, C6 cells (5×106) are inoculated subcutaneously into the hind flank. When the tumors reach approximately 250 mg (3-4 days postimplantation), rats are randomized (n=8 per group) and treated orally once daily for 12 days with Cabozantinib or water vehicle. Cabozantinib administered via oral gavage at 2 mL/kg. Body weights are collected daily, and tumor weights are collected twice weekly. Percentage of tumor growth inhibition/regression values are expressed as follows: 1−[(mean treated tumor weight on the final day−mean tumor weight on day 0)/(mean vehicle tumor weight on the final day−mean tumor weight on day 0)]×100. Statistical analysis of Cabozantinib-treated tumors versus vehicle-treated tumors or versus predose tumors is done by one-way ANOVA with significance defined as P<0.05. Blood is collected 4 hours after the final dose, and plasma is prepared to determine Cabozantinib concentrations. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    References
    Molecular Weight

    501.51

    Formula

    C₂₈H₂₄FN₃O₅

    CAS No.

    849217-68-1

    Storage
    Powder -20°C 3 years
      4°C 2 years
    In solvent -80°C 6 months
      -20°C 1 month
    Shipping

    Room temperature in continental US; may vary elsewhere

    Solvent & Solubility

    DMSO: ≥ 30 mg/mL

    Cabozantinib is prepared in 1.25% polyethylene glycol, 2.5% Tween-80, and 5% DMSO[3].

    * "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

    References

    Purity: 99.92%

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    Cabozantinib
    Cat. No.:
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