Cabozantinib (XL184, BMS-907351)

 

Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw

Biological Activity

Description	Cabozantinib (XL184, BMS-907351) 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 IC50 of 1.3 nM, 4 nM, 4.6 nM, 12 nM/11.3 nM/6 nM, 14.3 nM and 7 nM, respectively.
Targets	VEGFR2	c-Met	Ret	c-Kit	Flt-1/3/4	Tie2
IC50	0.035 nM	1.3 nM	4 nM	4.6 nM	12 nM/11.3 nM/6 nM	14.3 nM [1]
In vitro	XL184 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. [1] XL184 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. XL184 also induces marked inhibition of Met and VEGFR2 phosphorylation in cytokine-stimulated human umbilical vein endothelial cells (HUVECs). Although XL-184 has no significant effect on MPNST cell growth at 0.1 μM, XL184 at 5-10 μM significantly inhibits the MPNST cell growth. [2]
In vivo	XL184 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. XL184 also decreases invasiveness of primary tumors and reduces metastasis. [1] XL184 at 30 mg/kg/day significantly abrogates human MPNST xenografts growth and metastasis in SCID mice. [2] Administration of XL184 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 XL184 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. [3]
Features

Protocol(Only for Reference)

Cell Assay: 

^[2]

Cell lines	ST88-14, STS26T, and MPNST724
Concentrations	Dissolved in DMSO, final concentrations ~10 μM
Incubation Time	48 hours
Method	Cells are exposed to various concentrations of XL184 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.

Animal Study: 

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Animal Models	RIP-Tag2 transgenic mice in a C57BL/6 background with spontaneous pancreatic islet tumors
Dosages	~60 mg/kg
Administration	Oral gavage
Solubility	30% propylene glycol, 5% Tween 80, 65% D5W, 30 mg/mL

1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT01896479	Not yet recruiting	Medullary Thyroid Cancer	Exelixis	2013-12	Phase 4
NCT01995058	Recruiting	Prostate Cancer|Castration Resistant Prostate Cancer|Prostatic Neoplasms	Exelixis	2013-12	Phase 2
NCT02008383	Not yet recruiting	Colorectal Cancer	Duke University|John Strickler, M.D.|Exelixis, Inc	2014-01	Phase 1
NCT01979393	Not yet recruiting	Uterine Sarcoma	European Organisation for Research and Treatment of Cancer - EORTC|Gynecologic Oncology Group|NHS Greater Glasgow and Clyde	2014-01	Phase 2
NCT01630590	Not yet recruiting	Prostate Cancer	M.D. Anderson Cancer Center|Exelixis	2014-02	Phase 2

Chemical Information

Download Cabozantinib (XL184, BMS-907351) SDF

Chemical Name	N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.50151	5.0151	10.0302	15.0453

Customer Reviews (1)

Click to enlarge	Rating
	Source	Christina W Yde/CDM Danish Cancer Society Research Center Denmark. Cabozantinib (XL184, BMS-907351) purchased from Selleck
	Method	Cell growth assay
	Cell Lines	MCF-7 breast cancer cells
	Concentrations	0-1.5 μM
	Incubation Time	5 d
	Results	XL-184 potently inhibited the survival of MCF-7 cells in a dose-dependent manner.

Product Citations (3)

• 
  

  Kinase fusions are frequent in Spitz tumours and spitzoid melanomas [Wiesner T, et al. Nat Commun 2014;5:3116]

  
  PubMed: 24445538


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  Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase. [Mologni L, et al. Mol Cell Endocrinol 2013;377(1-2):1-6]

  
  PubMed: 23811235


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  Novel withanolides target medullary thyroid cancer through inhibition of both RET phosphorylation and the mammalian target of rapamycin pathway. [Samadi AK, et al. Surgery 2012;152(6):1238-47]

  
  PubMed: 23158190