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    CP-673451
    CP-673451

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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 #: V0577
    CAS #: 343787-29-1Purity ≥98%

    Description: CP-673451 (CP673451) is a novel, potent, selective and ATP-competitive inhibitor of PDGFR(α/β) with potential antitumor activity. It inhibits PDGFR(α/β) with IC50s of 10 nM/1 nM in cell-free assays and displays >450-fold selectivity for PDGFR(α/β) over other angiogenic receptors. CP-673451 has antiangiogenic and antitumor activity. and is being investigated to treat cancer. CP-673451 exhibits excellent anti-proliferative activity in vitro and high in vivo antitumor efficacy (at 20 mg/kg) with a medium suppression of tumor growth, while high-dose CP-673451 (40 mg/kg) strongly inhibits tumor growth in mice without significant weitht loss.

    References: Cancer Res. 2005 Feb 1;65(3):957-66; Cancer Res. 2013 Apr 1;73(7):2139-49. 

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    Molecular Weight (MW)417.5
    FormulaC24H27N5O2
    CAS No.343787-29-1
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 28 mg/mL (67.1 mM)
    Water: <1 mg/mL
    Ethanol: 4 mg/mL (9.56 mM)
    Solubility (In vivo)30% PEG 400+5% propylene glycol+1% Tween 80+ddH2O: 30mg/mL
    SynonymsCP-673451; CP673451; CP 673451; CP-673,451; CP 673,451 

    Chemical Name: 1-(2-(5-(2-Methoxyethoxy)benzimidazol-1-yl)quinolin-8-yl)piperidin-4-ylamine

    InChi Key: DEEOXSOLTLIWMG-UHFFFAOYSA-N

    InChi Code: InChI=1S/C24H27N5O2/c1-30-13-14-31-19-6-7-21-20(15-19)26-16-29(21)23-8-5-17-3-2-4-22(24(17)27-23)28-11-9-18(25)10-12-28/h2-8,15-16,18H,9-14,25H2,1H3

    SMILES Code: NC1CCN(C2=C3N=C(N4C5=CC=C(OCCOC)C=C5N=C4)C=CC3=CC=C2)CC1


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    In Vitro

    In vitro activity: CP 673451 is a selective inhibitor of PDGFRα/β with IC50 of 10 nM/1 nM, exhibits >450-fold selectivity over other angiogenic receptors. In glioblastoma tumors, CP-673451 (33 mg/kg) provides >50% inhibition of PDGFR-β receptor for 4 hours corresponding to an EC50 of 120 ng/mL in plasma at Cmax. In a sponge angiogenesis model, CP-673451 inhibits 70% of PDGF-BB-stimulated angiogenesis at a dose of 3 mg/kg (q.d. ×5, p.o., corresponding to 5.5 ng/mL at Cmax). CP-673451 decreases cell proliferation rate through mechanisms involving reduced phosphorylation of GSK-3α and GSK-3β. In both RD and RUCH2 cultures, CP-673451 impairs rhabdosphere-forming capacity and cell differentiation, causes increased senescence.


    Kinase Assay: A glutathione S-transferase-tagged kinase domain construct of the intracellular portion of the PDGFR-β (amino acids 693-1401, accession no. J03278) is expressed in Sf-9 cells (baculovirus expression system). Enzyme kinetics are determined by incubating the enzyme with increasing concentrations of ATP in phosphorylation buffer [50 mmol/L HEPES (pH 7.3), 125 mmol/L NaCl, 24 mmol/L MgCl2 in Nunc Immuno MaxiSorp 96-well plates previously coated with 100 μL of 100 μg/mL poly-Glu-Tyr (4:1 ratio) diluted in PBS. After 10 minutes, the plates are washed (PBS, 0.1% Tween 20), incubated with anti-phosphotyrosine-horseradish peroxidase antibody, and diluted in PBS, 0.05% Tween 20, 3% BSA for 30 minutes at room temperature. The plates are washed as above and incubated with 3,3',5,5'-tetramethylbenzidine. The reaction is stopped by adding an equal volume of 0.09 NaH2SO4. The phosphotyrosine-dependent signal is then quantitated on a plate reader at 450 nm. For routine enzyme assays, the enzyme is incubated with 10 μM ( final) ATP in the presence of compound diluted in DMSO (1.6% v/v DMSO assay final) for 30 minutes at room temperature in plates, as above, previously coated with 100 μL of 6.25 μg/mL poly-Glu-Tyr. The remainder of the assay is carried out as above, and IC50 values are calculated as percent inhibition of control.


    Cell Assay: PAE cells stably expressing full-length PDGFR and VEGFR have been generated. For cell-based selectivity assays, PAE cells are transfected with fulllength human PDGFR-a, PDGFR-h, or VEGFR-2. Cells are seeded at 4×105 cells/mL in 50 μL growth medium (Ham's F-12 media supplemented with 10% fetal bovine serum, 50,000 units each penicillin and streptomycin, and 500 μg/mL gentamicin) per well in 96-well plates. After 6 to 8 hours, the growth medium is replaced with 50 μL serum-depleted medium (as above, but with 0.1% fetal bovine serum) and cells are incubated overnight. Immediately before compound addition, the medium was replaced with 95 μL serum-depleted medium. Compounds are diluted in 100% DMSO, added to the cells at a final DMSO concentration of 0.25% v/v, and incubated at 37°C for 10 minutes. Cells are stimulated with the appropriate ligand and incubated as above for an additional 8 minutes. The medium is removed and the cells washed once with PBS, then lysed with 50 μL HNTG buffer [20 mmol/L HEPES (pH 7.5), 150 mmol/L NaCl, 2% Triton X-100, 10% glycerol, 5 μmol/L EDTA, 2 mmol/L NaVO4, and 1 EDTA-free complete protease inhibitor tablet per 25 mL] for 5 minutes at room temperature. Lysates are then diluted with 50 μL HG buffer [20 mmol/L HEPES (pH 7.5), 10% glycerol]. The diluted cell lysates are mixed thoroughly, 50 μL of supernatant are transferred to the ELISA capture plate, and incubated at room temperature for 2 hours with agitation. ELISA capture plates are prepared by coating 96-well ReactiBind goat-antirabbit plates with 100 μL/well of 5 μg/mL rabbit anti-human PDGFR-h, anti-PDGFR-a, or anti-VEGFR-2 antibody for 60 to 90 minutes. At the end of the 2-hour incubation the plates are washed (PBS, 0.1% Tween 20) before incubation with anti-phosphotyrosine-horseradish peroxidase antibody (diluted in PBS, 0.05% Tween 20) for 30 minutes at room temperature. The plates are washed again, then incubated with tetramethylbenzidine and evaluated as described above. IC50 values are calculated as percent inhibition of control.

    In VivoCP 673451 inhibits tumor growth (ED50 < 33 mg/kg) in a number of human tumor xenografts grown s.c. in athymic mice, including H460 human lung carcinoma, Colo205 and LS174T human colon carcinomas, and U87MG human glioblastoma multiforme. In RUCH2 xenograft-bearing mice, CP 673451 reduces tumor growth and stromal cell infiltration.
    Animal modelAthymic female mice
    Formulation & DosageDissolved in 5% Gelucire; 3, 10, or 33 mg/kg; oral gavage 
    References

     Cancer Res. 2005 Feb 1;65(3):957-66; Cancer Res. 2013 Apr 1;73(7):2139-49. 


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

    CP-673451


    CP-673451

    Impaired anchorage-independent rhabdosphere-forming capacity in cells devoid of PDGF activity. A, rhabdosphere formation in the presence of CP-673,451 or vehicle. B, rhabdosphere formation of cells pretreated 72 hours with CP-673,451 or vehicle in adherent cultures before seeding.

    CP-673451

    PDGFR inhibition reduces tumor growth and stromal cell infiltration. A, growth of RUCH2 xenografts in response to CP-673,451 or vehicle (n≥6 mice/group). Cancer Res. 2013 Apr 1;73(7):2139-49.


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