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    XL388
    XL388

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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 #: V0206
    CAS #: 1251156-08-7Purity ≥98%

    Description: XL388 is a novel, highly potent, selective, oral, ATP-competitive inhibitor of mTOR (mammalian target of rapamycin) with potential antitumor activity. It inhibits mTOR with an IC50 of 9.9 nM, and exhibits 1000-fold selectivity for mTOR over phosphatidylinositol 3-kinase (PI3K) . It showed potent antiproliferative activity in vitro and high antitumor efficacy in vivo. XL388 has favorable pharmacokinetic properties and oral bioavailability in multiple species. Oral gavage of XL388 to athymic nude micebearing human tumor xenografts achieved significant tumor suppression effects.

    References: J Med Chem. 2013 Mar 28;56(6):2218-34.   

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    Molecular Weight (MW)

    455.5

    Formula

    C23H22FN3O4S

    CAS No.

    1251156-08-7

    Storage

    -20℃ for 3 years in powder form

    -80℃ for 2 years in solvent

    Solubility (In vitro)

    DMSO: 23 mg/mL (50.5 mM)

    Water: <1 mg/mL

    Ethanol: <1 mg/mL

    Solubility (In vivo)

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

    Synonyms

    Synonym: XL388; XL 388; XL-388

    Chemical Name: (7-(6-aminopyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)(3-fluoro-2-methyl-4-(methylsulfonyl)phenyl)methanone

    InChi Key: LNFBAYSBVQBKFR-UHFFFAOYSA-N

    InChi Code: InChI=1S/C23H22FN3O4S/c1-14-18(5-7-20(22(14)24)32(2,29)30)23(28)27-9-10-31-19-6-3-15(11-17(19)13-27)16-4-8-21(25)26-12-16/h3-8,11-12H,9-10,13H2,1-2H3,(H2,25,26)

    SMILES Code: O=C(N1CCOC2=CC=C(C3=CC=C(N)N=C3)C=C2C1)C4=CC=C(S(=O)(C)=O)C(F)=C4C


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    In Vitro

    Kinase Assay: The measurement of mTOR enzyme activity is performed in an ELISA format following the phosphorylation of 4E-BP1 protein. All experiments are performed in the 384-well format. Generally, 0.5 μL of DMSO containing varying concentrations of the test compound is mixed with 15 μL of the enzyme solution. Kinase reactions are initiated with the addition of 15 μL of a solution containing the substrate. The assay conditions are as follows: 0.2 nM mTOR, 10 μM ATP, and 50 nM NHis-tagged 4E-BP1 in 20 mM Hepes, pH 7.2, 1 mM DTT, 50 mM NaCl, 10 mM MnCl2, 0.02 mg/mL BSA, 0.01% CHAPS, 50 mM β-glycerophophate. Following an incubation of 120 min at ambient temperature, 20 μL of the reaction mixture is transferred to a Ni-chelate-coated 384-well plate. The binding step of the 4E-BP1 protein proceeded for 60 min, followed by washing four times each with 50 μL of Tris-buffered saline solution (TBS). Anti-phospho-4E-BP1 rabbit immunoglobulin G (IgG; 20 μL, 1:5000) in 5% BSA-TBST (0.2% Tween-20 in TBS) is added, and the reaction mixuture is further incubated for 60 min. Incubation with a secondary horseradish peroxidase (HRP)-tagged anti-IgG is similarly performed after the primary antibody is washed off (four washes of 50 μL). Following the final wash step with TBST, 20 μL of SuperSignal ELISA Femto is added and the luminescence measured using an EnVision plate reader. Data are reported as the mean (n≥2) 

    Cell Assay: In MCF-7 cells, XL388 blocks mTORC1 phosphorylation of p70S6K (T389)with an IC50 value of 94 nM and blocks mTORC2 phosphorylationof AKT (S473) with an IC50 value of 350 nM. In vitro, XL388 inhibits the viability of solid and hematopoietic tumor cell lines. The proliferation IC50 is 1.37 μM in MCF-7 cell line. XL388 also synergizes with chemotherapeutics in cell-based assays to block cell viability.

    In Vivo

    When dosed orally once daily in mice, XL388 shows robust anti-tumor activity in multiple xenograft models including > 100% tumor growth inhibition in the MCF-7 xenograft model. XL388 displays good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. The mean plasma protein binding of XL388 in human, monkey, dog, rat, and mouse plasma is evaluated at 5 μM and is determined to be 86%, 90%, 89%, 85%, and 84%, respectively. Oral administration of XL388 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity. Strong inhibition of both mTORC1 and mTORC2 is achieved 4−8 h following administration orally at 100 mg/kg. Modest inhibition (39−45%) of phosphorylation of the PI3K target AKT (T308) is also observed 4−8 h post dose.

    Animal model

    MCF-7 xenograft tumors

    Formulation & Dosage

    Formulated in solution/fine suspension in water (with a 1:1 molar ratio of 1 N HCl); 50, 100 mg/kg; p.o.

    References

    J Med Chem. 2013 Mar 28;56(6):2218-34.


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

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