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Cabozantinib (XL184, BMS-907351)

VEGFR2/Met/Ret/Kit/FLT//AXL inhibitor CAS# 849217-68-1

Cabozantinib (XL184, BMS-907351)

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Cabozantinib (XL184, BMS-907351)

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Chemical Properties of Cabozantinib (XL184, BMS-907351)

Cas No. 849217-68-1 SDF Download SDF
PubChem ID 25102847 Appearance Powder
Formula C28H24FN3O5 M.Wt 501.51
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Cabozantinib, BMS 907351
Solubility DMSO : ≥ 30 mg/mL (59.82 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 1-N-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
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
Standard InChIKey ONIQOQHATWINJY-UHFFFAOYSA-N
Standard InChI InChI=1S/C28H24FN3O5/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/h3-11,14-16H,12-13H2,1-2H3,(H,31,33)(H,32,34)
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 (XL184, BMS-907351)

DescriptionPotent VEGFR inhibitor (IC50 = 0.035 nM); also inhibits c-Met, KIT, RET, FLT4, AXL, FLT3, FLT1 and Tie2 (IC50 values are 1.3, 4.6, 5.2, 6, 7, 11.3, 12 and 14.3 nM, respectively). Induces intratumoral hypoxia and apoptosis. Reduces tumor invasion and metastasis in vivo. Antiangiogenic.

Cabozantinib (XL184, BMS-907351) Dilution Calculator

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Preparing Stock Solutions of Cabozantinib (XL184, BMS-907351)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.994 mL 9.9699 mL 19.9398 mL 39.8796 mL 49.8495 mL
5 mM 0.3988 mL 1.994 mL 3.988 mL 7.9759 mL 9.9699 mL
10 mM 0.1994 mL 0.997 mL 1.994 mL 3.988 mL 4.9849 mL
50 mM 0.0399 mL 0.1994 mL 0.3988 mL 0.7976 mL 0.997 mL
100 mM 0.0199 mL 0.0997 mL 0.1994 mL 0.3988 mL 0.4985 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.

Research Update of Cabozantinib (XL184, BMS-907351)

1. Multi-targeted tyrosine kinase inhibitors in clinical development: focus on XL-184 (cabozantinib). Drugs Today (Barc). 2011 Nov;47(11):857-68. doi: 10.1358/dot.2011.47.11.1688487.
Abstract
XL-184 is an inhibitor of multiple receptor tyrosine kinases, particularly Met, VEGFR-2 and Ret, with clinical activities against tumors of both epithelial and mesenchymal origins, particularly medullary thyroid cancer and cancers metastatic to the bone.
3. Cabozantinib inhibits prostate cancer growth and prevents tumor-induced bone lesions. Clin Cancer Res. 2014 Feb 1;20(3):617-30. doi: 10.1158/1078-0432.CCR-13-0839. Epub 2013 Oct 4.
Abstract
XL-184, a multi-tyrosine kinase inhibitor targeting MET and VEGFR2, induces resolution of bone scan lesions in men with castration-resistant prostate cancer bone metastases possibly through a direct antitumor activity, modulating bone, or both.
4. A dose-ranging study of cabozantinib in men with castration-resistant prostate cancer and bone metastases. Clin Cancer Res. 2013 Jun 1;19(11):3088-94. doi: 10.1158/1078-0432.CCR-13-0319. Epub 2013 Apr 3.
Abstract
The efficacy and tolerability of XL-184, a MET/VEGFR2 inhibitor improving bone scans in mCRPC patients, at lower starting doses were determined due to XL-184 induced AE.
5. 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 Dec;23(12):1569-77. doi: 10.1089/thy.2013.0137. Epub 2013 Sep 17.
Abstract
XL-184, a multi-tyrosine kinase inhibitor targeting RET, MET and VEGFR2, inhibited activated RET mutations associated with MTC and effectively suppressed the growth of MTC tumor cell models both in vivo and in vitro.

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Background on Cabozantinib (XL184, BMS-907351)

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.

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References on Cabozantinib (XL184, BMS-907351)

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.[Pubmed:28013036]

Urology. 2017 Mar;101:169.e7-169.e13.

OBJECTIVE: To clarify the invasive mechanisms of muscle-invasive bladder cancer (BCa) would be useful for the determination of appropriate treatment strategies. We previously showed that hepatocyte growth factor (HGF)-MET signaling is correlated with invasiveness of BCa cells. Here, we investigated the effects of the MET inhibitor, cabozantinib (XL184), on BCa cells. METHODS: We first conducted Western blot analysis to investigate MET expression in BCa cell lines. Next, we examined the effect of cabozantinib on their proliferation and invasive abilities using MTT and Matrigel invasion assays, respectively. Invasion assays were performed using the xCELLigence system. Additionally, to investigate the biological function of HGF-MET signaling, we analyzed gene expression profiles and performed real-time polymerase chain reaction analyses of 5637 cells that were cultivated with or without HGF stimulation, with or without cabozantinib. RESULTS: MET was highly expressed in 4 of 5 BCa cell lines, and 5637 and T24 cells showed especially high protein expression of MET. Cabozantinib suppressed cell proliferation and invasion (cell index; mock, 1.49 vs HGF, 2.26 vs HGF + XL184, 1.47, P < .05). Gene expression profile analysis indicated that matrix metalloproteinase 1 (MMP1) was significantly elevated at the mRNA level with addition of HGF. Moreover, cabozantinib suppressed HGF-induced MMP1 expression in 5637 T24 cells. CONCLUSIONS: These data indicate that cabozantinib suppressed MMP1 expression by blocking HGF-MET signaling and that HGF-MET-MMP1 signaling is involved in the invasiveness and proliferation of BCa cells. These results suggest that cabozantinib might prove useful for future treatment of muscle-invasive BCa.

Cabozantinib (XL184) Inhibits Growth and Invasion of Preclinical TNBC Models.[Pubmed:26432786]

Clin Cancer Res. 2016 Feb 15;22(4):923-34.

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.

A phase I study of cabozantinib (XL184) in patients with differentiated thyroid cancer.[Pubmed:25102375]

Thyroid. 2014 Oct;24(10):1508-14.

BACKGROUND: Cabozantinib targets tyrosine kinases including MET, vascular endothelial growth factor (VEGF) receptor 2, and rearranged during transfection (RET). Differentiated thyroid cancer (DTC) is a tumor type that may be sensitive to cabozantinib. Therefore, we evaluated cabozantinib in a cohort of heavily pretreated patients with metastatic DTC. METHODS: This single-arm open-label phase I trial assessed the safety, tolerability, and antitumor activity of cabozantinib in DTC patients taking part in a drug-drug interaction study. Adult patients with histologically confirmed metastatic or surgically unresectable DTC (including papillary, follicular, or Hurthle cell) were enrolled. Patients received daily oral dosing of 140 mg cabozantinib. Safety was assessed by evaluation of adverse events (AEs), vital signs, electrocardiograms, laboratory tests, and concomitant medications. Tumor response by magnetic resonance imaging or computed tomography scan was investigator assessed using Response Evaluation Criteria In Solid Tumors (RECIST) v1.0. RESULTS: The study enrolled 15 patients who had failed standard radioactive iodine therapy. Patients had received a median of two prior systemic agents, and 11 patients (73%) had previously received at least one VEGF pathway inhibiting therapy. Common AEs included diarrhea, nausea, fatigue, and decreased appetite. Partial response was reported in eight patients (53%). Median progression-free survival and median overall survival were not reached. CONCLUSIONS: Cabozantinib demonstrates a safety profile similar to other multitargeted VEGFR inhibitors in advanced DTC patients. The antitumor activity observed in this study warrants further investigation of cabozantinib in patients with advanced DTC.

A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer.[Pubmed:28352985]

Cancer Chemother Pharmacol. 2017 May;79(5):923-932.

PURPOSE: Cabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib. METHODS: This was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent cabozantinib 100 mg qd vs cabozantinib 100 mg qd and erlotinib 50 mg qd (phase I MTD), with a primary objective of estimating objective response rate (ORR). RESULTS: Sixty-four patients were treated in phase I. Doses of 100 mg cabozantinib plus 50 mg erlotinib, or 40 mg cabozantinib plus 150 mg erlotinib were determined to be MTDs. Diarrhea was the most frequent dose-limiting toxicity and the most frequent AE (87.5% of patients). The ORR for phase I was 8.2% (90% CI 3.3-16.5). In phase II, one patient in the cabozantinib arm (N = 15) experienced a partial response, for an ORR of 6.7% (90% CI 0.3-27.9), with no responses for cabozantinib plus erlotinib (N = 13). There was no evidence that co-administration of cabozantinib markedly altered erlotinib pharmacokinetics or vice versa. CONCLUSIONS: Despite responses with cabozantinib/erlotinib in phase I, there were no responses in the combination arm of phase II in patients with acquired resistance to erlotinib. Cabozantinib did not appear to re-sensitize these patients to erlotinib.

VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer.[Pubmed:21613405]

Cancer Res. 2011 Jul 15;71(14):4758-68.

Angiogenesis inhibitors that block VEGF receptor (VEGFR) signaling slow the growth of many types of tumors, but eventually the disease progresses. Multiple strategies are being explored to improve efficacy by concurrent inhibition of other functionally relevant receptor tyrosine kinases (RTK). XL880 (foretinib, GSK1363089) and XL184 (cabozantinib) are small-molecule inhibitors that potently block multiple RTKs, including VEGFR and the receptor of hepatocyte growth factor c-Met, which can drive tumor invasion and metastasis. This study compared the cellular effects of XL880 and XL184 with those of an RTK inhibitor (XL999) that blocks VEGFR but not c-Met. Treatment of RIP-Tag2 mice with XL999 resulted in 43% reduction in vascularity of spontaneous pancreatic islet tumors over 7 days, but treatment with XL880 or XL184 eliminated approximately 80% of the tumor vasculature, reduced pericytes and empty basement membrane sleeves, caused widespread intratumoral hypoxia and tumor cell apoptosis, and slowed regrowth of the tumor vasculature after drug withdrawal. Importantly, XL880 and XL184 also decreased invasiveness of primary tumors and reduced metastasis. Overall, these findings indicate that inhibition of c-Met and functionally related kinases amplifies the effects of VEGFR blockade and leads to rapid, robust, and progressive regression of tumor vasculature, increased intratumoral hypoxia and apoptosis, and reduced tumor invasiveness and metastasis.

Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth.[Pubmed:21926191]

Mol Cancer Ther. 2011 Dec;10(12):2298-308.

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.

Description

Cabozantinib is a potent multiple receptor tyrosine kinases (RTKs) 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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