XL184 is a small molecule designed to inhibit multiple receptor tyrosine kinases, specifically MET and VEGFR2. MET is a receptor tyrosine kinase that plays key roles in cellular proliferation, migration, and invasion as well as angiogenesis. These biological processes contribute to the transformation, progression, survival and metastasis of cancer cells. The MET pathway is frequently activated in tumors through MET amplification, mutation, and overexpression, as well as through overexpression of its ligand HGF. Expression of VEGF has been observed in a variety of cancers and has been associated with the stimulation and growth of new blood vessels to support the tumor. MET and VEGFR2 are important driving forces in angiogenesis, implicated in the ability of tumors to overcome hypoxia following angiogenesis inhibition.
|Cell lines||ST-88, STS26T and MPNST724 cells line|
|Preparation method||Cell growth assays
MTS assays: these were conducted using CellTiter96 Aqueous Non-Radioactive Cell Proliferation Assay kit (Promega Corp, Madison, WI), per manufacturer's instructions. Drugs were administered at doses and for intervals as indicated. Absorbance was 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. Colony formation assay: one hundred viable cells per well were plated and allowed to grow in normal medium for 10 days and then stained for 30 min at room temperature with a 6% glutaraldehyde, 0.5% crystal violet solution. Pictures were captured digitally and colonies were counted. All experiments were repeated at a minimum twice for each cell line.
|Concentrations||0~10 µ M|
|Incubation time||48 h|
|Animal models||SCID mice bearing STS26T and MPNST724 xenografts|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Multi-targeted tyrosine kinase inhibitors in clinical development: focus on XL-184 (cabozantinib).
Bowles DW et al. Drugs Today (Barc). 2011 Nov;47(11):857-68. PMID: 22146228.
Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth.
Yakes FM et al. Mol Cancer Ther. 2011 Dec;10(12):2298-308. PMID: 21926191.
Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer.
Kurzrock R et al. J Clin Oncol. 2011 Jul 1;29(19):2660-6. PMID: 21606412.
|Related c-Met Products|
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S49076 is a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3 with IC50 values below 20 nmol/L.
Altiratinib(DCC-2701) is a novel c-MET/TIE-2/VEGFR inhibitor; effectively reduce tumor burden in vivo and block c-MET pTyr(1349)-mediated signaling, cell growth and migration as compared with a HGF antagonist in vitro.
MK-2461 is a potent, multi-targeted inhibitor for c-Met(WT/mutants) with IC50 of 0.4-2.5 nM, less potent to Ron, Flt1; 8- to 30-fold greater selectivity of c-Met targets versus FGFR1, FGFR2, FGFR3, PDGFRβ, KDR, Flt3, Flt4, TrkA, and TrkB.
NVP-BVU972 is a selective and potent Met inhibitor with IC50 of 14 nM.
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