BMS-777607 is a selective and potent small-molecule met kinase inhibitor. Overexpression of c-Met receptor tyrosine kinase has been highly associated with prostate cancer progression and metastasis. BMS-777607 suppressed HGF-stimulated cell migration and invasion in a dose-dependent fashion (IC50 < 0.1 μmol/L). Mechanistically, nanomolar doses of BMS 777607 potently blocked HGF-stimulated c-Met autophosphorylation and downstream activation of Akt and extracellular signal-regulated kinase.
|Source||Mol Oncol (2014). Figure 2. BMS-777607|
|Cell Lines||breast cancer cells|
|Incubation Time||72 h|
|Results||Thus, results demonstrate that expression of p21/WAF1 and survivin is up-regulated in BMS-777607 induced polyploid/senescent cells regardless the status of p53.|
|Source||Mol Oncol (2014). Figure 1. BMS-777607|
|Method||senescence detection assay|
|Cell Lines||BMS-777607. T-47D and ZR-75-1 cells|
|Incubation Time||72 h|
|Results||The percentages of SABG-positive cells were associated with increased doses of BMS-777607.|
|Cell lines||PC-3 cell line|
|Preparation method||Cell proliferation and cell death Cells were seeded in a 96-well plate at a density of 5 × 103 cells per well and exposed to serial dilutions of BMS-777607 for 1 hour. HGF (25 ng/mL) was then added and the cells were incubated (drug plus HGF) for a period of 96 hours. At the end of the treatment period, the tumor cells were exposed to WST-8 (MTT assay reagent) in a Cell Counting kit (Donjindo Molecular Technologies) according to the manufacturer's instruction, and absorbance was determined at 450 nm colorimetrically. Cell proliferation (%) was calculated as the ratio of absorbance from treated sample to the nontreated control. Cell death was examined by trypan blue exclusion, and positively stained (dead) cells were scored using a hemocytometer.|
|Concentrations||0, 0.1, 0.3, 1, 3, 10 μM|
|Incubation time||96 h|
|Animal models||C3H/HeJ mice with KHT lung tumor model|
|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.
|Solubility||DMSO 40 mg/mL|
Constitutively active c-Met kinase in PC-3 cells is autocrine-independent and can be blocked by the Met kinase inhibitor BMS-777607.
Dai et al. BMC Cancer. 2012 May 28;12(1):198. PMID: 22639908.
Impact of the small molecule Met inhibitor BMS-777607 on the metastatic process in a rodent tumor model with constitutive c-Met activation.
Dai et al. Clin Exp Metastasis. 2012 Mar;29(3):253-61. PMID: 22286523.
BMS-777607, a small-molecule met kinase inhibitor, suppresses hepatocyte growth factor-stimulated prostate cancer metastatic phenotype in vitro.
Dai et al. Mol Cancer Ther. 2010 Jun;9(6):1554-61. PMID: 20515943.
Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Schroeder et al. J Med Chem. 2009 Mar 12;52(5):1251-4. PMID: 19260711.
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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.
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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.
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