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    OSI-027 (ASP-4786, CERC-006, AEVI-006)
    OSI-027  (ASP-4786, CERC-006, AEVI-006)

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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 #: V0189
    CAS #: 936890-98-1 Purity ≥98%

    Description:OSI-027 (formerly known as ASP4786; AEVI006; CERC006) is a novel, potent, selective, orally bioavailable and ATP-competitive dual inhibitor of mTORC1 (mammalian target of rapamycin 1) and mTORC2 with potential anticancer activity. It inhibits mTORC1/2 with IC50 of 22 nM and 65 nM in cell-free assays, and showed more than 100-fold selectivity for mTOR over PI3Kα, PI3Kβ, PI3Kγ or DNA-PK. OSI-027 has potential antineoplastic activity and is being developed as an anticancer agent through inhibiting mTORC1 and mTORC2. In cellular assays, OSI-027 inhibits the phosphorylation of mTORC1 and mTORC2 substrates including AKT, PRAS40 and S6K1, which results in the blockade of downstream signaling. Dual inhibition of the mTOR kinase complexes mTORC1 and mTORC2 by OSI-27 decreases tumor xenograft growth in vivo and VEGF secretion in vitro.

    References: Cancer Res. 2011 Mar 1;71(5):1573-83; Clin Cancer Res. 2011 Jul 1;17(13):4378-88; Breast Cancer Res Treat. 2012 Aug;134(3):1057-66.  

    Related CAS: 1187559-64-3 (calcium salt); 1187559-66-5 (sodium); 1187559-73-4 (potassium) 

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    • 香港大学
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    Molecular Weight (MW)

    406.44

    Formula

    C21H22N6O3

    CAS No.

    936890-98-1 (free acid) ; 

    Storage

    -20℃ for 3 years in powder form

    -80℃ for 2 years in solvent

    Solubility (In vitro)

    DMSO: 18 mg/mL (44.3 mM)

    Water: <1 mg/mL

    Ethanol: <1 mg/mL

    Solubility (In vivo)

    1% DMSO+30% polyethylene glycol+1% Tween 80: 30mg/mL 

    Synonyms & Other info

     ASP4786; ASP 4786; ASP-4786; OSI027; OSI-027; OSI 027;

    Chemical Name: trans-4-[4-amino-5-(7-methoxy-1H-indol-2-yl)imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanecarboxylic acid

    InChi Key: JROFGZPOBKIAEW-HAQNSBGRSA-N

    InChi Code: InChI=1S/C21H22N6O3/c1-30-15-4-2-3-13-9-14(25-16(13)15)17-18-19(22)23-10-24-27(18)20(26-17)11-5-7-12(8-6-11)21(28)29/h2-4,9-12,25H,5-8H2,1H3,(H,28,29)(H2,22,23,24)/t11-,12-

    SMILES Code: O=C([[email protected]]1CC[[email protected]](C2=NC(C(N3)=CC4=C3C(OC)=CC=C4)=C5C(N)=NC=NN52)CC1)O



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    In Vitro

    Kinase Assay: mTORC1 and mTORC2 inhibition is assayed using native enzyme complex immunoprecipitated from HeLa lysates at 1 mM ATP. To prepare whole cell lysates from HeLa cells, 25 g cell pellet is lysed in 60 mL of ice-cold buffer A [40 mM HEPES (pH 7.5), 120 mM NaCl, 1 mM EDTA, 10 mM sodium pyrophosphate, 10 mM glycerophosphate, 50 mM NaF, 0.5 mM orthovanadate, and EDTA-free protease inhibitors containing 0.3% CHAPS] for 30 minutes on a magnetic stirrer in a cold room. After clearing of the lysates by centrifugation at 13,000 g for 10 minutes, Protein G-coated 384-well plates are incubated with 0.25 μg of mTOR antibody in 15 μL of buffer A for 1 hour at 4 °C. To each well, 40 μg of HeLa cell lysate in 15 μL of buffer A is added and incubated overnight at 4 °C to immunoprecipitate mTOR complexes. Plates are washed 3 times with buffer A and twice with immunoprecipitation wash buffer [Buffer B: 50 mM HEPES (pH 7.5) and 150 mM NaCl]. OSI-027 is added at 10 μM concentration to each well and DMSO is added to the control wells. The reaction is started by adding 150 ng of His-tagged 4E-BP1 as a substrate in the presence or absence of 100 μM ATP to each well in 25 μL of freshly prepared kinase buffer [Buffer C: 20 mM HEPES (pH 7.5), 10 mM MgCl2, 4 mM MnCl2, 10 mM β-mercaptoethanol, and 200 μM vanadate] and incubated at room temperature (RT) for 30 minutes. The reaction is stopped by transferring 25 μL of reaction mixture from each well to corresponding wells of fresh Ni-chelate-coated plates and incubated overnight at 4 °C followed by 2 hours at 37 °C. To detect phosphorylation of 4E-BP1, the plates are washed once with TBST (Tris-buffered saline containing 0.1% Tween-20) containing 5% skim milk powder. To each well, 25 μL of 1:1,000 diluted phospho-4E-BP1 antibodies in TBST containing 5% skim milk are added and incubated for 1 hour at RT. The plates are washed once with TBST and then 25 μL of anti-rabbit HRP (diluted 1:10,000) in TBST containing 5% skim milk is added. The plates are incubated for 1 hour at RT and washed 5 times with TBST. For detection of phospho-4E-BP1, 25 μL of chemiluminescent reagents A+B is added and chemiluminescence is measured using an Analyst plate reader.

     

    Cell Assay: Inhibition of proliferation is measured using the Cell Titer Glo Assay , as noted in figure legends. To generate dose–response curves, cell lines are seeded at a density of 5,000 cells per well in a 96-well plate. After 24 hours of plating, cells are dosed with varying concentrations of either OSI-027 or rapamycin. The signal for Cell Titer Glo Assay is determined 72 hours after dosing and normalized to that of vehicle-treated controls. Inhibition of proliferation, relative to vehicle-treated controls, is expressed as a fraction of 1 and graphed using PRISM software. Cell lines: U937, KG-1, KBM-3B, ML-1, HL-60, and MEG-01.

    OSI-027 shows the selective and ATP competitive inhibition activities against mTORC1 and mTORC2 with IC50 of 22 nM and 65 nM, respectively. In addition, OSI-027 inhibits mTOR signaling of phospho-4E-BP1 with an IC50 of 1 μM in cell-based assays. OSI-027 exhibits anti-proliferative activities against several acute leukemia cell lines of myeloid/megakaryocytic origin in a dose-dependent manner, including U937, KG-1, KBM-3B, ML-1, HL-60, and MEG-01 cells. A recent study shows that inhibition of mTORC1/2 by OSI-027 effectively suppresses phosphorylation of Akt (S473) and cell proliferation in breast cancer cells.

    In Vivo

    In GEO colorectal xenograft, OSI-027 (65 mg/kg) inhibits both mTORC1 and mTORC2 effectors, including 4E-BP1, Akt, and S6 phosphorylation. Furthermore, mTORC1 and mTORC2 inhibition together by OSI-027 potently inhibits tumor growth more than mTORC1 inhibition by rapamycin.

    Animal model

    GEO colorectal cells are injected s.c. into the right flank of nu/nu CD-1 mice.

    Formulation & Dosage

    Formulated in DMSO and then diluted in water.; 20 mg/kg; i.p. injection

    References

    Cancer Res. 2011 Mar 1;71(5):1573-83; Clin Cancer Res. 2011 Jul 1;17(13):4378-88; Breast Cancer Res Treat. 2012 Aug;134(3):1057-66.  


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

    OSI-027

    Effects of OSI-027, OXA-01, and rapamycin on tumor growth and pharmacodynamics.   2011 Mar 1;71(5):1573-83.

    OSI-027

    Anti-tumor effects of VEGFR2 plus mTORC1/2 inhibition.  2011 Mar 1;71(5):1573-83.

    OSI-027

    Effects of mTOR inhibition after cessation of VEGFR inhibition.  2011 Mar 1;71(5):1573-83.


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