VEGFR2 (IC50 = 0.035 nM); Flt-4 (IC50 = 6 nM); Flt-1 (IC50 = 12 nM); Met (IC50 = 1.3 ± 1.2 nM)

XL184 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. Moreover, XL184 lessens metastasis and the invasiveness of original tumors.[1] At 30 mg/kg/day, XL184 dramatically inhibits the growth and metastasis of human MPNST xenografts in SCID mice.[2] In models of breast, lung, and glioma tumors, the administration of XL184 results in a dose-dependent inhibition of tumor growth, along with a decrease in the proliferation of tumor and endothelial cells and an increase in apoptosis. For MDA-MB-231 tumor-bearing mice and C6 tumor-bearing rats, a single oral dosage of XL184 at 100 mg/kg and 10 mg/kg, respectively, is sufficient to cause long-term tumor growth inhibition.[3]

In addition to inhibiting c-Met, Ret, Kit, Flt-1/3/4, Tie2, and AXL with IC50 values of 1.3 nM, 4 nM, 4.6 nM, 12 nM/11.3 nM/6 nM, 14.3 nM, and 7 nM, respectively, cabotinib (XL184, BMS-907351) is a potent inhibitor of VEGFR2.

For 48 hours, different XL184 concentrations are applied to the cells. 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.

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

Absorption, Distribution and Excretion
After oral administration, peak plasma concentration was achieved in 2-5 hours.
Cabozantinib is eliminated mostly by the feces (54%) and also by the urine (27%).
The volume of distribution is 349L.
At steady state, the clearance is 4.4 L/hr.

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Metabolism / Metabolites
Cabozantinib is metabolized mostly by CYP3A4 and, to a minor extent, by CYP2C9. Both enzyme produce an N-oxide metabolite.

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Biological Half-Life
Cabozantinib has a long half-life of 55 hours.

Hepatotoxicity
In large clinical trials of cabozantinib, elevations in serum aminotransferase levels were common, occurring in 16% to 97% of patients. Values greater than 5 times the upper limit of normal (ULN), however, occurred in only 2% to 8% of recipients. Serum alkaline phosphatase elevations were also common and were above 3 times ULN in 3% of patients. Despite the high rate of serum enzyme elevations, cases of clinically apparent liver injury including acute liver failure were not reported in the preregistration trials of cabozantinib. Since the approval of cabozantinib, there have been no published case reports of hepatotoxicity attributed to its use. Serum ALT, AST and alkaline phosphatase elevations are listed as adverse reactions in the product label for cabozantinib, and cholestatic hepatitis is mentioned as a rare occurrence, but monitoring of serum enzymes during treatment is not specifically recommended.
Likelihood score: E* (Unproven but suspected rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
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.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Cabozantinib has extensive plasma protein binding (≥ 99.7%).

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

[2]. Clin Cancer Res . 2011 Jun 15;17(12):3943-55.

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

Cabozantinib is a dicarboxylic acid diamide that is N-phenyl-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide in which the hydrogen at position 4 on the phenyl ring is substituted by a (6,7-dimethoxyquinolin-4-yl)oxy group. A multi-tyrosine kinase inhibitor, used (as its malate salt) for the treatment of progressive, metastatic, medullary thyroid cancer. It has a role as a tyrosine kinase inhibitor and an antineoplastic agent. It is a member of quinolines, an organofluorine compound, an aromatic ether and a dicarboxylic acid diamide.
Cabozantinib was first approved in 2012 and is a non-specific tyrosine kinase inhibitor. It was initially approved in the US under the brand name Cometriq, which is indicated for the treatment of metastatic medullary thyroid cancer. In 2016, a capsule formulation (Cabometyx) was approved for the treatment of advanced renal cell carcinoma, and this same formulation gained additional approval in both the US and Canada in 2019 for the treatment of hepatocellular carcinoma in previously treated patients.
Cabozantinib is a Kinase Inhibitor. The mechanism of action of cabozantinib is as a Protein Kinase Inhibitor.
Cabozantinib is orally available kinase inhibitor and antineoplastic agent that is used in treatment of advanced, metastatic medullary thyroid cancer and refractory renal cell carcinoma. Cabozantinib is associated with a low rate of serum enzyme elevations during treatment and has been implicated with rare instances of clinically apparent, acute liver injury, some of which have been severe.
Cabozantinib is an orally bioavailable, small molecule receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. Cabozantinib strongly binds to and inhibits several RTKs, which are often overexpressed in a variety of cancer cell types, including hepatocyte growth factor receptor (MET), RET (rearranged during transfection), vascular endothelial growth factor receptor types 1 (VEGFR-1), 2 (VEGFR-2), and 3 (VEGFR-3), mast/stem cell growth factor (KIT), FMS-like tyrosine kinase 3 (FLT-3), TIE-2 (TEK tyrosine kinase, endothelial), tropomyosin-related kinase B (TRKB) and AXL. This may result in an inhibition of both tumor growth and angiogenesis, and eventually lead to tumor regression.
See also: Cabozantinib s-malate (has salt form).

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Drug Indication
Cabozantinib is indicated for the treatment of progressive, metastatic medullary thyroid cancer. It is also indicated for the treatment of advanced renal cell carcinoma and for hepatocellular carcinoma in patients previously treated with sorafenib.
FDA Label
Treatment of adult patients with progressive, unresectable locally advanced or metastatic medullary thyroid carcinoma.
Renal Cell Carcinoma (RCC)Cabometyx is indicated as monotherapy for the treatment of advanced renal cell carcinoma (RCC): in treatment-naïve adults with intermediate or poor risk,in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy. Cabometyx, in combination with nivolumab, is indicated for the first-line treatment of advanced renal cell carcinoma in adults. Hepatocellular Carcinoma (HCC)Cabometyx is indicated as monotherapy for the treatment of hepatocellular carcinoma (HCC) in adults who have previously been treated with sorafenib.
Treatment of solid malignant tumours

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Mechanism of Action
Cabozantinib inhibits specific receptor tyrosine kinases such as VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, RET, MET, and TIE-2.

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Pharmacodynamics
Cabozantinib suppresses metastasis, angiogenesis, and oncognesis by inhibiting receptor tyrosine kinases.

C28H24FN3O5

501.51

501.17

C, 67.06; H, 4.82; F, 3.79; N, 8.38; O, 15.95

849217-68-1

Cabozantinib S-malate;1140909-48-3;Cabozantinib-d6;1802168-46-2;Cabozantinib hydrochloride;1817759-42-4;Cabozantinib-d4;1802168-53-1

25102847

white solid powder

1.4±0.1 g/cm3

758.1±60.0 °C at 760 mmHg

412.3±32.9 °C

0.0±2.6 mmHg at 25°C

1.688

4.84

2

7

8

37

795

0

O=C(C1(CC1)C(NC1C=CC(OC2C3C(=CC(=C(C=3)OC)OC)N=CC=2)=CC=1)=O)NC1C=CC(F)=CC=1

ONIQOQHATWINJY-UHFFFAOYSA-N

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)

1-N-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Cabozantinib; XL-184; BMS-907351; BMS907351; XL184; XL 184; BMS 907351; Cabozantinib free base; trade name Cometriq

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.98 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.15 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: 2.08 mg/mL (4.15 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 4: ≥ 2.08 mg/mL (4.15 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL corn oil and mix evenly.

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Solubility in Formulation 5: 2% DMSO +30%PEG 300 +5% Tween 80 +ddH2O: 2mg/mL

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Solubility in Formulation 6: 2.5 mg/mL (4.98 mM) in 0.5% CMC/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)