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Cabozantinib malate (XL184)

MET andVEGF receptor2 inhibitor CAS# 1140909-48-3

Cabozantinib malate (XL184)

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Cabozantinib malate (XL184)

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Chemical Properties of Cabozantinib malate (XL184)

Cas No. 1140909-48-3 SDF Download SDF
PubChem ID 25102846 Appearance Powder
Formula C32H30FN3O10 M.Wt 635.59
Type of Compound N/A Storage Desiccate at -20°C
Synonyms XL184; Cabozantinib
Solubility DMSO : ≥ 23 mg/mL (36.19 mM)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
Chemical Name 1-N-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;(2S)-2-hydroxybutanedioic acid
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.C(C(C(=O)O)O)C(=O)O
Standard InChIKey HFCFMRYTXDINDK-WNQIDUERSA-N
Standard InChI InChI=1S/C28H24FN3O5.C4H6O5/c1-35-24-15-21-22(16-25(24)36-2)30-14-11-23(21)37-20-9-7-19(8-10-20)32-27(34)28(12-13-28)26(33)31-18-5-3-17(29)4-6-18;5-2(4(8)9)1-3(6)7/h3-11,14-16H,12-13H2,1-2H3,(H,31,33)(H,32,34);2,5H,1H2,(H,6,7)(H,8,9)/t;2-/m.0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Cabozantinib malate (XL184)

DescriptionCabozantinib (S-malate) is a potent VEGFR2 inhibitor with IC50 of 0.035 nM, and also inhibits c-Met, Ret, Kit, Flt-1/3/4, Tie2, and AXL with IC50s of 1.3 nM, 4 nM, 4.6 nM, 12 nM/11.3 nM/6 nM, 14.3 nM and 7 nM, respectively.In Vitro:XL184 (0.1-0.5μM) inhibits the constitutive and inducible MET phosphorylation and its resultant downstream signaling in all MPNST cells. XL184 (> 0.1μM) elicits a significant MPNST cell growth inhibition; higher XL184 doses are needed to inhibit NSC growth. XL184 treatment blocks HGF-induced MPNST motility and invasion (a similar effect of found on NSC)[2]. 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. Cabozantinib also inhibits tubule formation in response to conditioned media derived from cultures of MDA-MB-231 (IC50=5.1 nM), A431 (IC50=4.1 nM), HT1080 (IC50=7.7 nM), and B16F10 (IC50=4.7 nM) cells[3].In Vivo:Cabozantinib (60 mg/kg, i.p.) decreases the tumor vascularity with reductions ranging from 67% at 3 mg/kg to 83% at 30 mg/kg for 7 days in animals. Tumors in RIP-Tag2 mice treated for 7 days beginning at age 10 weeks are 40% smaller after XL880 and 35% smaller after XL184, compared to corresponding values for vehicle[1]. XL184 (30 mg/kg) significantly decreases the microvessel density in mice[2]. Cabozantinib (100 mg/kg, p.o.) inhibits in vivo stimulation of MET phosphorylation by HGF in liver hepatocytes and VEGF-stimulated phosphorylation of FLK1 with inhibition of both targets sustained through 8 hours postdose. Cabozantinib (100 mg/kg, p.o.) disrupts tumor vasculature and promotes tumor and endothelial cell death. Cabozantinib (1-60 mg/kg, p.o.) inhibits tumor growth and promotes tumor regression in vivo[3].

References:
[1]. You WK, et al. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res, 2011, 71(14), 4758-4768. [2]. Torres KE, et al. Activated MET is a molecular prognosticator and potential therapeutic target for malignant peripheral nerve sheath tumors. Clin Cancer Res, 2011, 17(12), 3943-3955. [3]. Yakes FM, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther, 2011, 10(12), 2298-2308.

Protocol

Kinase Assay [3]
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 half maximal inhibitory concentration (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.

Cell Assay [3]
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.

Animal Administration [3]
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 (SC161) and Western blotting with anti-phosphotyrosine MET (pY1230/34/35). After blot stripping, total MET is quantitated as a loading control. In a separate experiment, naive mice (n=5 per group) are administered a single 100 mg/kg dose of cabozantinib or vehicle, followed by intravenous administration of HGF (10 μg per mouse) 10 minutes before liver collection. Analysis of MET phosphorylation in liver lysates is as described above. In a separate experiment, naive mice (n=5 per group) are administered a single 100 mg/kg dose of cabozantinib or vehicle, followed by intravenous administration of VEGF (10 μg per mouse) 30 minutes before lung collection. Pooled lung lysates are subjected to immunoprecipitation with FLK1 (SC6251) and Western blotting with anti-phosphotyrosine (4G10). After blot stripping, total FLK1 is quantitated as a loading control.

References:
[1]. You WK, et al. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res, 2011, 71(14), 4758-4768. [2]. Torres KE, et al. Activated MET is a molecular prognosticator and potential therapeutic target for malignant peripheral nerve sheath tumors. Clin Cancer Res, 2011, 17(12), 3943-3955. [3]. Yakes FM, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther, 2011, 10(12), 2298-2308.

Cabozantinib malate (XL184) Dilution Calculator

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Preparing Stock Solutions of Cabozantinib malate (XL184)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.5733 mL 7.8667 mL 15.7334 mL 31.4668 mL 39.3335 mL
5 mM 0.3147 mL 1.5733 mL 3.1467 mL 6.2934 mL 7.8667 mL
10 mM 0.1573 mL 0.7867 mL 1.5733 mL 3.1467 mL 3.9334 mL
50 mM 0.0315 mL 0.1573 mL 0.3147 mL 0.6293 mL 0.7867 mL
100 mM 0.0157 mL 0.0787 mL 0.1573 mL 0.3147 mL 0.3933 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Cabozantinib malate (XL184)

Cabozantinib malate is a potent inhibitor of MET andVEGF receptor2 with IC50 values of 1.3nM and 0.035nM [1].

Cabozantinib is a pan-tyrosine kinase inhibitor and is developed as an oral treatment of various cancers including MTC, GBM, NSCLC, pancreatic carcinoma, breast and colon cancer. The targets of cabozantinib are MET, VEGFR-2, RET, FLT3, KIT, AXL as well as TEK. In cellular assays, cabozantinib inhibits the phosphorylation of MET, VEGFR2, KIT, FLT3 and AXL with IC50 values of 7.8, 1.9, 5.0, 7.5 and 42μM, respectively [1, 2].

As a pan-tyrosine kinase inhibitor, cabozantinib can affect many biological processes. Cabozantinib inhibits the tubule formation of HMVEC cells with IC50 value of 6.7nM. In B16F10 cells, cabozantinib inhibits HGF-inducedmigration and invasion with IC50 values of 31nM and 9nM, respectively. Moreover, cabozantinib shows anti-proliferation efficacy in a variety of tumors such as SNU-5, Hs746T, MDA-MB-231 and U87MG. It is also reported that the combination of cabozantinib and gefitinib can cause potent inhibition of the gefitinib-resistant HCC827GR6 cell line [1, 2].

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.
[2] Zhang Y, Guessous F, Kofman A, et al. XL-184, a MET, VEGFR-2 and RET kinase inhibitor for the treatment of thyroid cancer, glioblastoma multiforme and NSCLC. IDrugs, 2010, 13(2): 112.

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Description

Cabozantinib S-malate (XL184 S-malate) is a potent multiple receptor tyrosine kinases inhibitor that inhibits VEGFR2, c-Met, Kit, Axl and Flt3 with IC50s of 0.035, 1.3, 4.6, 7 and 11.3 nM, respectively.

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