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    PHA-680632
    PHA-680632

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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 #: V0360
    CAS #: 398493-79-3Purity ≥98%

    Description: PHA-680632 (PHA680632) is a novel and potent pan-aurora kinase inhibitor with potential antitumor activity. It inhibits Aurora A/B/C with IC50s of 27 nM, 135 nM and 120 nM, respectively, and shows 10- to 200-fold higher selectivity for aurora over FGFR1, FLT3, LCK, PLK1, STLK2, and VEGFR2/3. Moreover, PHA 680632 shows potent in vitro antiproliferative activity and high in vivo antitumor efficacy. It potently inhibits proliferation of various cancer cells including HCT116, A2780, HL60 and Hela cells with IC50 values in the nanomolar to micromolar range (0.06 to 7.15 μM).

    ReferencesClin Cancer Res. 2006 Jul 1;12(13):4080-9; Br J Cancer. 2007 Dec 17;97(12):1664-72.

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    • 香港大学
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    Molecular Weight (MW)501.62
    FormulaC28H35N7O2
    CAS No.398493-79-3
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 100 mg/mL (199.4 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)10% Tween 80: 30 mg/mL
    Synonyms

    Synonym: PHA 680632; PHA-680632; PHA 680632.

    Chemical Name: N-(2,6-diethylphenyl)-3-(4-(4-methylpiperazin-1-yl)benzamido)pyrrolo[3,4-c]pyrazole-5(1H,4H,6H)-carboxamide

    InChi Key: OBWNXGOQPLDDPS-UHFFFAOYSA-N

    InChi Code: InChI=1S/C28H35N7O2/c1-4-19-7-6-8-20(5-2)25(19)29-28(37)35-17-23-24(18-35)31-32-26(23)30-27(36)21-9-11-22(12-10-21)34-15-13-33(3)14-16-34/h6-12H,4-5,13-18H2,1-3H3,(H,29,37)(H2,30,31,32,36)

    SMILES Code: O=C(N(C1)CC2=C1C(NC(C3=CC=C(N4CCN(C)CC4)C=C3)=O)=NN2)NC5=C(CC)C=CC=C5CC


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    In Vitro

    In vitro activity: PHA-680632 potently inhibits all three Aurora kinases (A, B, and C) with IC50 values of 27, 135, and 120 nM, respectively. PHA-680632 is selective for Aurora kinases, with 10- to 200-fold higher IC50 for FGFR1, FLT3, LCK, PLK1, STLK2, VEGFR2, and VEGFR3, and with IC50 higher than 10 μM for another 22 kinases. PHA-680632 shows potent anti-proliferative effects in a wide range of cell types with IC50 values of 0.06–7.15 μM, including HeLa, HCT116, HT29, LOVO, DU145, and NHDF cells. PHA-680632 (0.5 μM) causes polyploidy in tumor cells. The mechanism of action of PHA-680632 is in agreement with inhibition of Aurora kinases. PHA680632 in association with radiation leads to additive effects in cancer cells, especially in the p53-deficient cells. Combined ionising radiation (IR) and treatment of PHA680632 (100–400 nM) prior to IR leads to an enhancement of radiation-induced Annexin V positive cells, micronuclei formation, and Brca1 foci formation only in HCT116 cells with deficient p53, other than the p53 wild-type counterparts.


    Kinase Assay: Inhibition of kinase activity by PHA-680632 is assessed using a scintillation proximity assay format. The biotinylated substrate is transphosphorylated by the kinase in presence of ATP traced with γ33-ATP. The phosphorylated substrate is then captured using streptavidin-coated scintillation proximity assay beads and the extent of phosphorylation is evaluated by β-counter after a 4-hour rest for the floatation of the beads on a dense 5 M CsCl solution. In particular, a peptide derived from the Chocktide sequence (LRRWSLGL) is used as substrate for Aurora A, whereas the optimized peptide Auroratide is employed for Aurora B and C. The assay is run in a robotized format on 96-well plates. The potency of the compound toward Aurora kinases is evaluated and IC50 values are determined.


    Cell Assay:  Cells (Colo205, SW620, HCT116, HT29, KW12, Hela, A2780, OVCAR8, MDA-MB-157 and MV4-11 cell lines) are treated with a range of 0 to 50 uM of CCT129202 for 72 hours. Cell proliferation is analyzed with the colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The absorbance is measured at 570 nm using the Wallac VICTOR2TM 1420 Multilabel

    In VivoHA-680632 (15–60 mg/kg) inhibits tumor growth in mice xenografts models of HL60, A2780, and HCT116 cells, by reducing tumor cell proliferation and increasing apoptosis. PHA-680632 (45 mg/kg) suppresses growth of activated ras-driven mammary tumors in mouse mammary tumor virus v-Ha-ras transgenic mice and results in complete tumor stabilization and partial regression.
    Animal modelMice (female athymic nude) xenografts models of p53−/− HCT116 cells
    Formulation & DosageDissolved in 20% Tween-80 in 5% glucose solution; 40 mg/kg; i.p. injection BID
    References

    Clin Cancer Res. 2006 Jul 1;12(13):4080-9; Br J Cancer. 2007 Dec 17;97(12):1664-72.


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

    PHA-680632

    Influence of PHA680632 on cell cycle in p53wt vs p53−/− HCT116 cells. Br J Cancer. 2007 Dec 17; 97(12): 1664–1672.

    PHA-680632

    In vivo tumour growth delay after PHA680632 and irradiation. Br J Cancer, 2007, 97(12), 1664-1672.


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