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    PF-03814735
    PF-03814735

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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 #: V0366
    CAS #: 942487-16-3Purity ≥98%

    Description: PF-03814735 (PF03814735) is a reversible, orally bioavailable, and ATP-competitive inhibitor of Aurora A/B kinases with potential antitumor activity. It inhibits Aurora A/B with IC50of 0.8 nM and 5 nM, respectively. PF-03814735 showed less potency against Flt3, FAK, TrkA, Met and FGFR1. It exhibits potent in vitro antiproliferative activity and high in vivo antitumor efficacy.

    ReferencesMol Cancer Ther. 2010 Apr;9(4):883-94; Mol Cancer Ther. 2012 Mar;11(3):710-9.

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    Molecular Weight (MW)474.48
    FormulaC23H25F3N6O2
    CAS No.942487-16-3
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 0.4 mg/mL (0.84 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)2% Cremophor EL, 2% N,N-dimethylacetamide, pH 5.0: ~30 mg/mL
    Synonyms

    PF-03814735; PF 03814735; PF03814735

    Chemical Name: N-(2-((1S,4R)-6-((4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1,2,3,4-tetrahydro-1,4-epiminonaphthalen-9-yl)-2-oxoethyl)acetamide

    InChi Key: RYYNGWLOYLRZLK-RBUKOAKNSA-N

    InChi Code: InChI=1S/C23H25F3N6O2/c1-12(33)27-11-20(34)32-18-7-8-19(32)16-9-14(5-6-15(16)18)30-22-28-10-17(23(24,25)26)21(31-22)29-13-3-2-4-13/h5-6,9-10,13,18-19H,2-4,7-8,11H2,1H3,(H,27,33)(H2,28,29,30,31)/t18-,19+/m0/s1

    SMILES Code: CC(NCC(N1[[email protected]@]2([H])CC[[email protected]]1([H])C3=C2C=CC(NC4=NC=C(C(F)(F)F)C(NC5CCC5)=N4)=C3)=O)=O 


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    In Vitro

    In vitro activity: In intact cells, the inhibitory activity of PF-03814735 on the Aurora1 and Aurora2 kinases reduces levels of phospho-Aurora1 (Thr 232, a sensitive marker of Aurora1 activity, with IC50 ~ 20 nM), phosphohistone H3 (with IC50 ~ 50 nM), and phospho-Aurora2 (with IC50 ~150 nM). PF-03814735 produces a block in cytokinesis, resulting in inhibition of cell proliferation and the formation of polyploid multinucleated cells. A recent research indicates small cell lung cancer (SCLC) and, to a lesser extent, colon cancer lines are very sensitive to PF-03814735. The status of the Myc gene family and retinoblastoma pathway members significantly correlates with the efficacy of PF-03814735.


    Kinase Assay: Aurora1 and Aurora2 proteins are produced as full-length His-tag recombinant proteins expressed in insect cells. For the Aurora2 kinase assay, phosphorylation of the substrate peptide by recombinant Aurora2 protein is assessed by a Z'-LYTE assay at 3 to 300 μM ATP and various concentrations of PF-03814735 over 60 minutes, at a substrate peptide concentration of 2 μM (biotinylated LRRWSLG, ×4). Phosphorylation is linear over this time for all conditions. For the Aurora1 kinase assay, phosphorylation of the substrate peptide by recombinant Aurora1 protein is assessed by a scintillation proximity assay in a 96-well plate format in which the incorporation of 33P into the peptide substrate (biotinylated LRRWSLG, ×4) is measured by capturing the peptide on a streptavidin scintillation proximity assay bead.


    Cell Assay: Cell lines (HCT-116 cell) are grown in appropriate media and evaluated after 48 h of exposure to either PF-03814735 or vehicle, followed by cell number determination in a Coulter Counter. Proliferation (as measured by an increase in cell number) is expressed as a percent of untreated controls. To evaluate the PF-03814735 exposure time required for antiproliferative activity, HL-60 cell cultures are cultured in RPMI medium supplemented with 15% heat-inactivated fetal bovine serum and exposed to various PF-03814735 concentrations for 4, 8, 12, 24, and 48 hours, followed by a washout step and incubation with growth media without PF-03814735 for the remainder of the 72-h assay period. Continuous exposure to PF-03814735 for 72 hours is also evaluated. Cell counts are determined by a Coulter Counter.

    In VivoOnce-daily oral dosing of ≥20 mg/kg of PF-03814735 for 10 days to mice bearing HCT-116 xenografts resulted in statistically significant and dose-dependent tumor growth inhibition of ≥50% relative to vehicle-treated mice. The inhibition is associated with a reduction in phosphorylated histone H3 levels. Significant single-agent antitumor efficacy is observed in five additional xenograft tumor models, including A2780 ovarian carcinoma, MDA-MB-231 breast carcinoma, colo-205 and SW620 colorectal carcinomas, and HL-60 acute promyelocytic leukemia. In vivo experiments with two SCLC xenograft models confirms the sensitivity of Myc gene-driven models to PF-03814735 and a possible schedule dependence of MYC/c-Myc-driven tumors.
    Animal modelHCT116 tumors are implanted s.c. on the right flank of nude mice.
    Formulation & DosageDissolved in cremophor EL [cremophor/ethanol/0.9% saline (12.5%/12.5%/75%)]; 10, 20, 30 mg/kg;  Oral gavage
    References

    Mol Cancer Ther. 2010 Apr;9(4):883-94; Mol Cancer Ther. 2012 Mar;11(3):710-9.


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

    PF-03814735

    PF-03814735 activity in a cell panel correlated with the status of pathway genes and major cancer drivers. Mol Cancer Ther.2012 Mar;11(3):710-9. 

    PF-03814735

    Effect of MYC downregulation on sensitivity to PF-03814735. Mol Cancer Ther. 2012 Mar;11(3):710-9.

    PF-03814735

    Effect of PF-03814735 on growth of NCI-H82 and NCI-H69 SCLC xenografts. Mol Cancer Ther.2012 Mar;11(3):710-9.


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