Cabozantinib malate (XL184) 1140909-48-3

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Molecular Weight:

635.59 Cabozantinib malate is the malate of Cabozantinib, 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 IC50 of 1.3 nM, 4 nM, 4.6 nM, 12 nM/11.3 nM/6 nM, 14.3 nM and 7 nM, respectively.


Biological Activity


Cabozantinib has weak inhibitory activity against RON and PDGFRβ with
IC50 of 124 nM and 234 nM, respectivey, and has low activity against
FGFR1 with IC50 of 5.294 μM. Cabozantinib at low
concentration (0.1-0.5 μM) is sufficient to induce marked inhibition of
constitutive and inducible Met phosphorylation and its resultant
downstream signaling in MPNST cells, and inhibit HGF-induced MPNST cell
migration and invasion.


Cabozantinib also induces marked inhibition of
Met and VEGFR2 phosphorylation in cytokine-stimulated human umbilical
vein endothelial cells (HUVECs). Although Cabozantinib has no
significant effect on MPNST cell growth at 0.1 μM, Cabozantinib at 5-10
μM significantly inhibits the MPNST cell growth.


Cabozantinib treatment at 30 mg/kg in RIP-Tag2 mice with spontaneous
pancreatic islet tumors disrupts 83% of the tumor vasculature, reduces
pericytes and empty basement membrane sleeves, causes widespread
intratumoral hypoxia and extensive tumor cell Apoptosis, and slows
regrowth of the tumor vasculature after drug withdrawal, more
significantly compared with XL999 that blocks VEGFR but not c-Met,
leading to only 43% reduction in vascularity, suggesting that concurrent
inhibition of VEGFR and other functionally relevant receptor tyrosine
kinases (RTK) amplifies Angiogenesis inhibition.


Cabozantinib also
decreases invasiveness of primary tumors and reduces metastasis. Cabozantinib at 30 mg/kg/day significantly abrogates human MPNST xenografts growth and metastasis in SCID mice. Administration of Cabozantinib induces dose-dependent inhibition of
tumor growth in breast, lung, and glioma tumor models, in association
with decreased tumor and endothelial cell proliferation as well as
increased apoptosis. A single oral dose of Cabozantinib is sufficient to
induce sustained tumor growth inhibition in MDA-MB-231 tumor-bearing
mice and C6 tumor-bearing rats at 100 mg/kg and 10 mg/kg, respectively.


Method






Cells are exposed to various concentrations of Cabozantinib for 48
hours. Cell growth is determined by MTS assays using CellTiter96 Aqueous
Non-Radioactive Cell Proliferation Assay kit. Absorbance is measured at
a wavelength of 490 nm, and the absorbance values of treated cells are
presented as a percentage of the absorbance of untreated cells.

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Product Categories : Protein Tyrosine Kinase > c-Met Inhibitor