ArtNr |
S1070-10 |
Hersteller |
Selleckchem
|
CAS-Nr. |
477575-56-7 |
Menge |
10 mg |
Kategorie |
|
Typ |
Inhibitors |
Specific against |
other |
ECLASS 10.1 |
32160490 |
ECLASS 11.0 |
32160490 |
UNSPSC |
12000000 |
Alias |
477575-56-7' |
Similar products |
PHA-665752 |
Lieferbar |
|
Administration |
Injection via bolus i.v. |
Animal Models |
Female athymic mice (nu/nu) bearing S114 or GTL-16 tumor xenografts |
Cell lines |
S114, GTL-16, NCI-H441, and BxPC-3 |
Chemical Name |
(R, Z)-5-(2, 6-dichlorobenzylsulfonyl)-3-((3, 5-dimethyl-4-(2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl)-1H-pyrrol-2-yl)methylene)indolin-2-one |
Concentrations |
Dissolved in DMSO, final concentrations ca.10 uM |
Description |
PHA-665752 is a potent, selective and ATP-competitive c-Met inhibitor with IC50 of 9 nM. |
Dosages |
ca.30 mg/kg/day |
Formulation |
Formulated in vehicle (L-lactate (pH 4.8) and 10% polyethylene glycol) |
IC50 |
9 nM [1], 9 nM [1], 9 nM [1], 9 nM [1], 9 nM [1], 9 nM [1] |
In vitro |
PHA-665752 significantly inhibits c-Met kinase activity with Ki of 4 nM, and exhibits >50-fold selectivity for c-Met compared with various tyrosine and serine-threonine kinases. PHA-665752 potently inhibits the HGF-stimulated c-Met autophosphorylation with IC50 of 25-50 nM. PHA-665752 also significantly blocks HGF- and c-Met-dependent functions such as cell motility and cell proliferation with IC50 of 40-50 nM and 18-42 nM, respectively. In addition, PHA-665752 potently inhibits HGF-stimulated or constitutive phosphorylation of mediators of downstream of c-Met such as Gab-1, ERK, Akt, STAT3, PLC-gamma, and FAK in multiple tumor cell lines. [1] PHA-665752 inhibits cell growth in TPR-MET-transformed BaF3 cells with IC50 of <60 nM, and inhibits constitutive cell motility and migration by 92.5% at 0.2 uM. Inhibition of c-Met by PHA665752 (0.2 uM) also induces cell apoptosis of 33.1% and G1 cell cycle arrest with cells in G1 phase increasing from 42.4% to 77.0%. PHA665752 can cooperate with rapamycin to inhibit cell growth of TPR-MET-transformed BaF3 cells and non-small cell lung cancer H441 cells. [2] |
In vivo |
Administration of PHA-665752 induces a dose-dependent tumor growth inhibition of S114 xenografts by 20 %, 39% and 68%, at dose of 7.5, 15, and 30 mg/kg/day, respectively. [1] PHA665752 treatment significantly reduces the tumor growth of NCI-H69, NCI-H441 and A549 in mouse xenografts by 99%, 75%, and 59%, respectively. PHA665752 also significantly inhibits angiogenesis by >85%, due to decreasing the production of vascular endothelial growth factor and increasing the production of the angiogenesis inhibitor thrombospondin-1. [3] |
Incubation Time |
18, or 72 hours |
Kinase Assay |
In vitro enzyme assay, The c-Met kinase domain GST-fusion protein is used for the c-Met assay. The IC50 value of PHA-665752 for the inhibition of c-Met is based on phosphorylation of kinase peptide substrates or poly-glu-tyr in the presence of ATP and divalent cation (MgCl2 or MnCl2 10-20 mM). The linear range (i.e., the time period over which the rate remains equivalent to the initial rate) is determined for c-Met, and the kinetic measurement and IC50 determination are performed within this range. |
Method |
For proliferation assays, cells are grown in medium with 0.1% FBS for 48 hours after which they are treated with various concentrations of PHA-665752 in HGF (50 ng/mL) in a medium containing 2% FBS. After 18 hours, cells are incubated with BrdUrd for 1 hour, fixed, and stained with anti-BrdUrd peroxidase-conjugated antibody, and plates are read at 630 nm. For apoptosis assays, cells are grown in medium with 2% FBS in presence and absence of HGF (50 ng/mL) and various concentrations of PHA-665752 for 72 hours. After 72 hours, a mixture containing ethidium bromide and acridine orange is added, and apoptotic cells (bright orange cells or cell fragments) are counted by fluorescence microscopy. |
Molecular Weight (MW) |
641, 61 |
Picture ChemicalStructure Description |
PHA-665752 Chemical Structure |
Picture Description 1 |
Data independently produced by, , , Dr. Zhang, of Tianjin Medical University, PHA-665752purchased from Selleck, Western blot analysis of p-c-Met and c-Met. 0-100M PHA665752 was added. |
Solubility (25C) |
DMSO 128 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL |
Storage |
2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO |
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