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.
|Source||Pharma Res (2017). Figure 5. XL-184|
|Method||ABCG2 ATPase assay|
|Cell Lines||H460, H460/MX20 cells|
|Incubation Time||72 h|
|Results||As shown in Fig 5, the subcellular distribution of ABCG2 incubated with cabozantinib for 72 hours did not change compared to the cells incubated in the absence of cabozantinib.|
|Source||Pharma Res (2017). Figure 3. XL-184|
|Method||[3H]-MX accumulation and efflux assay|
|Cell Lines||H460 and H460/MX20 cell line|
|Incubation Time||2 h|
|Results||As Shown in Fig 3, incubation of H460 cells with or without 5 μM of cabozantinib did not alter intracellular accumulation of MX. However, in the H460/MX20 cell line, 5 μM cabozantinib could significantly increase the fluorescence of MX inside the cells.|
|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.
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CEP-40783 (RXDX-106) is a potent, selective and orally available inhibitor of AXL and c-Met with IC50 values of 7 nM and 12 nM, respectively.
Savolitinib (volitinib, AZD6094, HMPL-504) is a novel, potent, and selective MET inhibitor currently in clinical development in various indications, including PRCC. The IC50 values of this compound for c-Met and p-Met are 5 nM and 3 nM, respectively. It shows exquisite selectivity for c-Met over 274 kinase.
AMG 337 is an oral, small molecule, ATP-competitive, highly selective inhibitor of the MET receptor.
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