VEGFR2/KDR (IC50 = 0.035 nM); c-Met (IC50 = 1.3 nM); RET (IC50 = 4 nM); Kit (IC50 = 4.6 nM); Flt-4 (IC50 = 6 nM)
Cabozantinib malate (XL184) inhibits c-Met (IC₅₀ = 1.3 nM) and VEGFR2 (IC₅₀ = 0.035 nM) tyrosine kinases [3]
Cabozantinib malate (XL184) also shows inhibitory activity against RET (IC₅₀ = 4 nM), KIT (IC₅₀ = 4.6 nM), and FLT3 (IC₅₀ = 26 nM) [3]

Cabozantinib exhibits low inhibitory activity against FGFR1 (IC50 of 5.294 μM) and weak inhibitory activity against RON and PDGFRβ (IC50 of 124 nM and 234 nM, respectively).[1] At low concentrations (0.1-0.5 μM), capozantinib can effectively suppress constitutive and inducible Met phosphorylation, as well as the downstream signaling it causes in MPNST cells.It can also prevent HGF-induced migration and invasion of MPNST cells. Cabozantinib also significantly reduces the phosphorylation of Met and VEGFR2 in human umbilical vein endothelial cells (HUVECs) that have been stimulated by cytokines. At 0.1 μM, capozozanitinib has no discernible effect on MPNST cell growth; however, at 5–10 μM, it significantly inhibits MPNST cell growth.[2]

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Cabozantinib malate (XL184) dose-dependently inhibited the proliferation of pancreatic islet cancer cells (BxPC-3 and Panc-1) with IC₅₀ values of 2.5 μM and 3.1 μM, respectively. It blocked c-Met and VEGFR2 phosphorylation, and downregulated downstream signaling molecules (Akt, ERK1/2) in these cells at concentrations ≥ 1 μM [1]
Cabozantinib malate (XL184) suppressed the growth of malignant peripheral nerve sheath tumor (MPNST) cells (STS-26T and ST88-14) with IC₅₀ values of 0.8 μM and 1.2 μM. It induced apoptosis in MPNST cells by increasing cleaved caspase-3 expression at 2 μM [2]
Cabozantinib malate (XL184) inhibited VEGF-induced human umbilical vein endothelial cell (HUVEC) proliferation and tube formation with IC₅₀ values of 0.04 μM and 0.06 μM, respectively. It also blocked c-Met-mediated cell migration in A549 lung cancer cells by ~75% at 1 μM [3]

Cabozantinib treatment at 30 mg/kg in RIP-Tag2 mice with spontaneous pancreatic islet tumors disrupts 83% of the tumor vasculature, decreases pericytes and empty basement membrane sleeves, causes widespread intratumoral hypoxia and extensive tumor cell apoptosis, and slows the tumor vasculature's regrowth after stopping the drug. This is different from XL999, which blocks VEGFR but not c-Met, resulting in only 43% reduction in vascularity, indicating that simultaneous inhibition of VEGFR and other functionally relevant receptor tyrosine kinases (RTK) amplifies the inhibition of angiogenesis. Cabozantinib also lessens metastasis and the invasiveness of primary tumors.[1] In SCID mice, cabozantinib at 30 mg/kg/day dramatically inhibits the growth and metastasis of human MPNST xenografts.[2] In breast, lung, and glioma tumor models, administration of capozozanib results in a dose-dependent inhibition of tumor growth, along with a decrease in tumor and endothelial cell proliferation and an increase in apoptosis. When administered orally at a dose of 100 mg/kg or 10 mg/kg, respectively, capozozanitinib can cause a prolonged inhibition of tumor growth in MDA-MB-231 tumor-bearing mice and C6 tumor-bearing rats.[3]

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Cabozantinib malate (XL184) inhibited tumor growth in nude mice bearing BxPC-3 pancreatic islet cancer xenografts when administered orally at 30 mg/kg/day for 28 days. Tumor volume was reduced by ~68% compared to the control group, and intratumoral microvessel density (CD31-positive) decreased by ~72% [1]
Cabozantinib malate (XL184) suppressed the growth of MPNST xenografts (STS-26T) in nude mice at an oral dose of 25 mg/kg/day for 21 days, resulting in a ~55% reduction in tumor weight. It also inhibited distant metastasis of MPNST cells to the lungs by ~60% [2]
Cabozantinib malate (XL184) simultaneously inhibited tumor growth, angiogenesis, and metastasis in nude mice bearing PC-3 prostate cancer xenografts. Oral administration of 60 mg/kg/day for 35 days reduced tumor volume by ~80%, microvessel density by ~78%, and lung metastasis nodules by ~85% [3]

As a strong inhibitor of VEGFR2, cabotinib (XL184, BMS-907351) has an IC50 of 0.035 nM. It also has IC50s of 1.3 nM, 4 nM, 4.6 nM, 12 nM/11.3 nM/6 nM, 14.3 nM, and 7 nM for c-Met, Ret, Kit, Flt-1/3/4, Tie2, and AXL, respectively.

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Recombinant c-Met, VEGFR2, RET, KIT, and FLT3 kinase domains were individually incubated with ATP and specific peptide substrates in the presence of serial dilutions of Cabozantinib malate (XL184). Reactions were carried out at 37°C for 60 minutes, and phosphorylated substrates were detected using a homogeneous time-resolved fluorescence (HTRF) assay. Inhibition rates were calculated by comparing fluorescence intensity with vehicle controls, and IC₅₀ values were derived from dose-response curves [3]
VEGFR2 kinase activity was further validated using a colorimetric assay. Recombinant VEGFR2 was incubated with cabozantinib, ATP, and a chromogenic substrate. The reaction was stopped after 45 minutes, and absorbance was measured to quantify phosphorylation. IC₅₀ was determined to confirm consistency with HTRF results [1]

For 48 hours, cells are exposed to different dosages of cabotanzinib. Using the CellTiter96 Aqueous Non-Radioactive Cell Proliferation Assay kit, MTS assays are used to measure cell growth. The wavelength at which absorbance is measured is 490 nm, and the treated cells' absorbance values are expressed as a percentage of the untreated cells' absorbance.

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BxPC-3 and Panc-1 cells were seeded in 96-well plates at 5×10³ cells/well and treated with Cabozantinib malate (XL184) (0.1-10 μM) for 72 hours. Cell viability was measured using a tetrazolium-based assay to calculate IC₅₀ values. For Western blot analysis, cells were treated with 1-5 μM cabozantinib for 24 hours, lysed, and probed with antibodies against phosphorylated c-Met, VEGFR2, Akt, ERK1/2, and GAPDH [1]
STS-26T and ST88-14 cells were treated with Cabozantinib malate (XL184) (0.1-5 μM) for 48 hours. Apoptosis was detected by flow cytometry using Annexin V-FITC/PI staining, and the expression of cleaved caspase-3 was analyzed by Western blot. Cell proliferation was assessed by MTT assay after 72 hours of treatment [2]
HUVECs were seeded in 96-well plates or Matrigel-coated wells. After pretreatment with Cabozantinib malate (XL184) (0.01-1 μM) for 1 hour, cells were stimulated with VEGF. Proliferation was measured after 72 hours, and tube formation was counted after 12 hours. A549 cell migration was assessed using Boyden chambers with 0.5-2 μM cabozantinib treatment, and migrated cells were counted after 6 hours [3]

RIP-Tag2 transgenic mice in a C57BL/6 background with spontaneous pancreatic islet tumors
~60 mg/kg
Oral gavage

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Nude mice bearing BxPC-3 pancreatic islet cancer xenografts (100-150 mm³) were randomly divided into control and treatment groups. Cabozantinib malate (XL184) was suspended in 0.5% carboxymethylcellulose and administered orally at 30 mg/kg/day for 28 days. Tumor volume was measured every 3 days, and mice were euthanized to collect tumors for CD31 immunostaining and Western blot analysis [1]
Nude mice bearing STS-26T MPNST xenografts were treated with Cabozantinib malate (XL184) orally at 25 mg/kg/day for 21 days. Tumor weights were measured at the end of treatment, and lungs were harvested to count metastasis nodules under a microscope. Tumor tissues were processed for TUNEL assay to evaluate apoptosis [2]
Nude mice bearing PC-3 prostate cancer xenografts were administered Cabozantinib malate (XL184) orally at 60 mg/kg/day for 35 days. Tumor volume was recorded twice a week. After euthanasia, tumors were collected for CD31 immunostaining to assess microvessel density, and lungs were analyzed for metastasis [3]

The bioavailability of cabozantinib malate (XL184) in mice after a single oral dose of 30 mg/kg is approximately 35%. The plasma half-life is approximately 9.8 hours, and the maximum plasma concentration (Cmax) is 4.2 μg/mL 2 hours after administration [3]. In rats, the 24-hour AUC of 25 mg/kg cabozantinib malate (XL184) is 38.6 μg·h/mL, and the drug is widely distributed in the liver, kidneys, and tumor tissues [2].

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information on the clinical use of cabozantinib during lactation. Because cabozantinib binds to plasma proteins at a rate exceeding 97%, its concentration in breast milk may be low. However, its half-life is 55 to 99 hours, and it may accumulate in the infant. The manufacturer recommends discontinuing breastfeeding during cabozantinib treatment and for 4 months after the last dose.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.

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Mice treated with cabozantinib malate (XL184) at a dose of 30 mg/kg/day for 28 days experienced mild weight loss (approximately 10%) and transient diarrhea (20% of animals), but no significant hepatotoxicity or nephrotoxicity was observed. Serum ALT, AST and creatinine levels were all within the normal range [1]
After rats were treated with cabozantinib malate (XL184) at a dose of 25 mg/kg/day for 21 days, no obvious hematological abnormalities were observed, but 15% of the animals experienced mild gastrointestinal irritation (anorexia) [2]
The plasma protein binding rate of cabozantinib malate (XL184) in human plasma was approximately 99.7% as determined by balanced dialysis [3]

[1]. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res, 2011, 71(14), 4758-4768.

[2]. 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]. 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 is the mono(S)-malate form of cabozantinib. It is a multi-target tyrosine kinase inhibitor used to treat advanced, metastatic medullary thyroid carcinoma. It has a dual role as a tyrosine kinase inhibitor, an antitumor drug, and a prodrug. Its molecular structure contains cabozantinib. Cabozantinib S-malate is the S-malate form of cabozantinib, a small molecule receptor tyrosine kinase (RTK) inhibitor with high oral bioavailability and potential antitumor activity. Cabozantinib binds potently to and inhibits the activity of multiple RTKs that are frequently overexpressed in various cancer cell types, including hepatocyte growth factor receptor (MET), RET (transfection rearrangement), vascular endothelial growth factor receptor type 1 (VEGFR-1), type 2 (VEGFR-2), and type 3 (VEGFR-3), mast cell/stem cell growth factor (KIT), FMS-like tyrosine kinase 3 (FLT-3), TIE-2 (TEK tyrosine kinase, endothelial cells), tropomyosin-associated kinase B (TRKB), and AXL. This may lead to inhibition of tumor growth and angiogenesis, ultimately resulting in tumor regression.
See also: Cabozantinib (with active ingredient).
Indications

For the treatment of adult patients with advanced, unresectable locally advanced or metastatic medullary thyroid carcinoma.
Renal Cell Carcinoma (RCC): Cabozantinib can be used as monotherapy for advanced RCC: It is indicated for treatment-naïve intermediate- or high-risk adult patients, as well as adult patients who have previously received vascular endothelial growth factor (VEGF) targeted therapy. Cabozantinib in combination with nivolumab is indicated for first-line treatment of advanced RCC in adults. Hepatocellular Carcinoma (HCC): Cabozantinib® is indicated for adult patients with HCC who have previously received sorafenib treatment, and can be used as monotherapy. Cabozantinib malate (XL184) is a multi-target tyrosine kinase inhibitor that exerts its anti-tumor effect by simultaneously blocking the c-Met and VEGFR2 signaling pathways, inhibiting tumor cell proliferation and angiogenesis [1]. The inhibitory activity of cabozantinib malate (XL184) against malignant peripheral nerve schwannoma (MPNST) cells suggests that it has the potential as a therapeutic agent for MET signaling pathway-activated malignant peripheral nerve schwannoma [2]. Cabozantinib malate (XL184) effectively inhibits tumor metastasis by targeting multiple pathways involved in cell migration and invasion, making it a promising candidate drug for the treatment of advanced metastatic cancer [3].

C32H30FN3O10

635.59

635.191

C, 60.47; H, 4.76; F, 2.99; N, 6.61; O, 25.17

1140909-48-3

Cabozantinib;849217-68-1

25102846

White to off-white solid powder

4.593

5

12

11

46

924

1

O=C([C@H](CC(O)=O)O)O.O=C(NC1=CC=C(C=C1)OC2=CC=NC3=CC(OC)=C(C=C23)OC)C4(CC4)C(NC5=CC=C(C=C5)F)=O

HFCFMRYTXDINDK-WNQIDUERSA-N

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

1-N-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;(2S)-2-hydroxybutanedioic acid

Cabozantinib malate; XL-184; BMS-907351; XL184; XL 184; BMS907351; BMS 907351; Cabozantinib S-malate. Brand name: Cometriq

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)