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    PF-4708671
    PF-4708671

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    产品仅用于科学研究,不针对患者销售
    数量: - + 件(库存件)
    InvivoChem目录号 #: V0239
    CAS号码 #: 1255517-76-0纯度 ≥98%

    Description: PF-4708671 is a novel, potent, highly specific and cell-permeable inhibitor of p70 ribosomal S6 kinase (S6K1 isoform)/RSK1 with potential antitumor activity. It inhibits RSK1 with a Ki/IC50 of 20 nM/160 nM in cell-free assays, exhibits 400-fold greater selectivity for S6K1 over S6K2, and displays 4- and >20-fold selectivity for S6K1 than MSK1 and RSK1/2, respectively. As the first S6K1-specific inhibitor reported, PF-4708671 showed potent antiproliferative activity in vitro and high antitumor efficacy in vivo by preventing the S6K1-mediated phosphorylation of S6 protein in response to IGF-1 (insulin-like growth factor 1), while having no effect upon the PMA-induced phosphorylation of substrates of the highly related RSK (p90 ribosomal S6 kinase) and MSK (mitogen- and stress-activated kinase) kinases.  

    References:Biochem J. 2010 Oct 15;431(2):245-55.

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    Molecular Weight (MW)

    390.41

    Formula

    C19H21F3N6

    CAS No.

    1255517-76-0

    Storage

    -20℃ for 3 years in powder form

    -80℃ for 2 years in solvent

    Solubility (In vitro)

    DMSO: 30 mg/mL (76.8 mM)

    Water: <1 mg/mL

    Ethanol: 8 mg/mL (20.5 mM)

    Solubility (In vivo)

    30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/mL

    Synonyms

    PF-4708671; PF4708671; PF 4708671

    Chemical Name: 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole

    SMILES Code: FC(C1=CC=C2NC(CN3CCN(C4=NC=NC=C4CC)CC3)=NC2=C1)(F)F

    Exact Mass: 390.17798 


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    In Vitro

    In vitro activity: PF-4708671 is a piperazinyl-pyrimidine analogue and the first S6K1-specific inhibitor. PF-4708671 does not significantly inhibit the activity of the closely related S6K2 isoform or a number of other AGC kinases (Akt1, Akt2, PKA, PKCα, PKCϵ, PRK2, ROCK2, RSK1, RSK2 or SGK1) . PF-4708671 prevents the S6K1-mediated phosphorylation of S6 protein in response to IGF-1 (insulin-like growth factor 1), while having no effect upon the PMA-induced phosphorylation of substrates of the highly related RSK (p90 ribosomal S6 kinase) and MSK (mitogen- and stress-activated kinase) kinases. PF-4708671 is also found to induce phosphorylation of the T-loop and hydrophobic motif of S6K1, an effect that is dependent upon mTORC1 (mTOR complex 1). PF-4708671 does not affect activity of mTORC1.

     

    Kinase Assay: PF-4708671 is a cell-permeable inhibitor of p70 ribosomal S6 kinase (S6K1 isoform) with Ki/IC50 of 20 nM/160 nM in cell-free assays, 400-fold greater selectivity for S6K1 than S6K2, and 4- and >20-fold selectivity for S6K1 than MSK1 and RSK1/2, respectively.

     

    Cell Assay: The effects of OSI-906 or the combination of OSI-906 and PF-4708671 on cell proliferation is determined with XTT and clonogenic assays (GEO, HT29, SW480, and HCT116 cells are used). XTT assays are performed using the Cell Proliferation Kit II (XTT). For clonogenic assays, cells (1×103cells/well) are seeded on a 6-well plate and subsequently treated with drugs (OSI-906 5 μM, PF-4708671 10 μM). After 1 week of incubation, cells are stained with 1% crystal violet, and the number of colonies is counted and recorded.

    In Vivo

    The tumor growth rate in mice treated with the combination of OSI-906+PF-4708671 is significantly slower than that of OSI-906 alone (P=0.0189) or PF4708671 alone (P=0.0165) treated mice. The average tumor volume in the OSI-906+PF-4708671-treated mice is approximately 50% of that in mice treated with OSI-906 (P=0.0056) or PF-4708671 alone (P<0.001) at the end of a 15-day treatment.

    Animal model

    Female athymic nude mice

    Formulation & Dosage

    60 mg/kg; oral

    References

    Biochem J. 2010 Oct 15;431(2):245-55.


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

    PF-4708671

    Pdcd4 enhances cell sensitivity to OSI-906 via suppression of p70S6K1 phosphorylation.   2015 Mar;14(3):799-809.

    PF-4708671

    The combination of OSI-906 and PF-4708671 significantly inhibits the growth of resistant CRC cells.  2015 Mar;14(3):799-809.

    PF-4708671

    The combination of OSI-906 and PF-4708671 significantly inhibits the growth of HCT116-derived tumor in nude mice.  2015 Mar;14(3):799-809.

    PF-4708671

    Expression level of Pdcd4 correlates with cell sensitivity to OSI-906.  2015 Mar;14(3):799-809.

    PF-4708671

    Tumors derived from Pdcd4 knockdown cells resist to OSI-906 treatment.  2015 Mar;14(3):799-809.

    PF-4708671


    Knockdown of p70S6K1 but not p70S6K2 enhances cell sensitivity to OSI-906.  2015 Mar;14(3):799-809.


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