JNJ-38877605 is a small-molecule, ATP-competitive inhibitor of the catalytic activity of c-Met. JNJ-38877605 showed f600-fold selectivity for c-Met compared with a panel of f250 diverse tyrosine and serine-threonine kinases and was found to potently inhibit HGF-stimulated and constitutively activated c-Met phosphorylation in vitro. In addition, JNJ-38877605 induces regression of U87-MG xenografts in vivo.
|Source||Int J Clin Exp Med (2015). Figure 4. JNJ-38877605|
|Cell Lines||PC-3 human prostate cancer cells|
|Concentrations||0.125 nM, 0.5 nM, 1 nM, 2.5 nM, 5 nM, 10 nM|
|Incubation Time||48 h|
|Results||However, different concentrations of saracatinib, linsitinib and JNJ-38877605 did not inhibit PC-3 cells proliferation after 48 h, high or low concentrations of the three inhibitors did not inhibit PC-3 cells proliferation at all.|
|Cell lines||S114, GTL-16, NCI-H441, or BxPC-3 cells|
|Preparation method||Cell Proliferation Assays. S114, GTL-16, NCI-H441, or BxPC-3 cells were seeded in 96-well plates at 9000 cells/well in medium with 10% FBS. After incubation for 48 h in low serum (0.5% FBS, S114; 0.1% FBS, GTL-16, NCI-H441, and BxPC-3), cells were treated with different concentrations of PHA-665752 for 18 h at 37°C. HGF (50 ng/ml) was added for 18 h before BrdUrd for studies involving GTL-16, H441, and BxPC-3. After incubation with BrdUrd labeling reagent for 1 h (Sigma Biochemicals, St. Louis, MO), cells were fixed and BrdUrd incorporation into newly synthesized DNA was assessed using anti-BrdUrd peroxidase-conjugated antibody followed by colorimetric determination at 630 nm.|
|Incubation time||18 h|
|Animal models||Female athymic mice bearing S114 or GTL-16 tumor xenografts|
|Formulation||L-lactate (pH 4.8) and 10% polyethylene glycol|
|Dosages||25 mg/kg a single i.v. dose|
|Administration||via bolus i.v. tail vein injection|
|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.
Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer.
De Bacco F, et al. J Natl Cancer Inst. 2011 Apr 20;103(8):645-61. PMID: 21464397.
Genetic and expression analysis of MET, MACC1, and HGF in metastatic colorectal cancer: response to met inhibition in patient xenografts and pathologic correlations.
Galimi F, et al. Clin Cancer Res. 2011 May 15;17(10):3146-56. PMID: 21447729.
|Related c-Met Products|
NPS-1034 is a dual inhibitor of Axl and MET with IC50 values of 10.3 and 48 nM, respectively.
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.
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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