NVP-BVU972 is a selective and potent MET kinase inhibitor with an IC50 of 14 nM. NVP-BVU972 potently inhibits MET kinase but displays low inhibition against other kinases including the most closely related kinase RON with IC50 values of more than 1000 nM. NVP-BVU972 also suppresses constitutive MET phosphorylation in GTL-16 cells or HGF-stimulated MET phosphorylation in A549 cells with IC50 values of 7.3 and 22 nM, respectively. NVP-BVU972 potently prevents the growth of the MET gene amplified cell linse GTL-16, MKN-45 and EBC-1 with IC50 values of 66, 82 and 32 nM, respectively. In good agreement with their high frequency in the NVP-BVU972 screen, Y1230 and D1228 mutations causes dramatic shifts in the measured IC50 values for NVP-BVU972 in BaF3 cell line. Resistance triggered by V1155L is more limited to NVP-BVU972.A dose-dependent reduction in TPR-MET phosphorylation when applying NVP-BVU972 to BaF3 cells expressing wild-type TPR-MET. Both Y1230H and D1228A mutations abrogated the effect of NVP-BVU972 but not AMG 458. However, F1200I and L1195V interferes with the potency of NVP-BVU972 to prevent TPR-MET phosphorylation.
|Cell lines||BaF3 cells|
|Preparation method||BaF3 cells containing TPR-MET or various mutants thereof are grown in RPMI 1640 medium containing 10% fetal calf serum. For maintenance of parental BaF3 cells the medium is additionally supplemented with 10 ng/mL interleukin-3 (IL-3). For proliferation assays, BaF3 cells are seeded on 96-well-plates in triplicates at 104 cells per well and incubated with various concentrations of NVP-BVU972 for 72 hours followed by quantification of viable cells using a resazurin sodium salt dye reduction readout. IC50 values are determined with the XLFit Excel Add-In using a 4-parameter dose response model.|
|Incubation time||72 hours|
|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 60 mg/mL|
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