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    PHA-665752
    PHA-665752

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0591
    CAS #: 477575-56-7Purity ≥98%

    Description: PHA-665752 (PHA665752) is a novel, potent, selective and ATP-competitive small molecule inhibitor of c-Met Kinase with potential antitumor activity. It inhibits c-Met with an IC50 of 9 nM in cell-free assays, and shows >50-fold selectivity for inhibiting c-Met over other kinases such as RTKs or STKs. It sas therapeutic potential of targeting c-Met overactivated human cancers. It shows potent anti-proliferative activity in vitro by suppressing the hepatocyte growth factor-induced cell proliferation and radioresistance in nasopharyngeal carcinoma cells. 

    References: Cancer Res. 2003 Nov 1;63(21):7345-55; Clin Cancer Res. 2005 Mar 15;11(6):2312-9; Cancer Res. 2007 Apr 15;67(8):3529-34.

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    Molecular Weight (MW)641.61
    FormulaC32H34Cl2N4O4S
    CAS No.477575-56-7
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 128 mg/mL (199.5 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)2% DMSO+castor oil: 5 mg/mL
    Other infoSynonym: PHA-665752; PHA665752; PHA 665752
    Chemical Name: (R,Z)-5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-(2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl)-1H-pyrrol-2-yl)methylene)indolin-2-one
    InChi Key: OYONTEXKYJZFHA-SSHUPFPWSA-N
    InChi Code: InChI=1S/C32H34Cl2N4O4S/c1-19-29(35-20(2)30(19)32(40)38-14-6-7-21(38)17-37-12-3-4-13-37)16-24-23-15-22(10-11-28(23)36-31(24)39)43(41,42)18-25-26(33)8-5-9-27(25)34/h5,8-11,15-16,21,35H,3-4,6-7,12-14,17-18H2,1-2H3,(H,36,39)/b24-16-/t21-/m1/s1
    SMILES Code: O=C1NC2=C(C=C(S(=O)(CC3=C(Cl)C=CC=C3Cl)=O)C=C2)/C1=C/C4=C(C)C(C(N5[[email protected]@H](CN6CCCC6)CCC5)=O)=C(C)N4  


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    In Vitro

    In vitro activity: 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-γ, and FAK in multiple tumor cell lines. 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 μM. Inhibition of c-Met by PHA665752 (0.2 μM) 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.


    Kinase 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.


    Cell Assay:  For proliferation assays, cells (S114, GTL-16, NCI-H441, and BxPC-3) 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.

    In VivoAdministration 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. 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.
    Animal modelFemale athymic mice (nu/nu) bearing S114 or GTL-16 tumor xenografts
    Formulation & DosageDissolved in vehicle (L-lactate (pH 4.8) and 10% polyethylene glycol); 30 mg/kg; i.v. injection
    References

    Cancer Res. 2003 Nov 1;63(21):7345-55; Clin Cancer Res. 2005 Mar 15;11(6):2312-9; Cancer Res. 2007 Apr 15;67(8):3529-34.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    PHA-665752

    PHA-665752
    PHA-665752


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