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    Alisertib (MLN8237, MLN-8237)
    Alisertib (MLN8237, MLN-8237)

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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 #: V0343
    CAS #: 1028486-01-2Purity ≥98%

    Description: Alisertib (also named as MLN8237, MLN-8237) is a novel potent, selective, orally bioavailable Aurora A kinase (AAK) inhibitor with potential antitumor activity. It inhibits Aurora A kinase with an IC50 of 1.2 nM in a cell-free assay and exhibits >200-fold higher selectivity for Aurora A than Aurora B. Alisertib shows potent in vitro antiproliferative activity and high in vivo antitumor efficacy. Alisertib was developed from its predecessor, MLN8054, in order to minimize the benzodiazepine-like effects seen with MLN8054. The inhibitory effect of Alisertib is ATP-competitive, reversible and AAK-specific with an inhibition constant (Ki) of 0.43 nmol/L. MLN8237 is being investigated to treat advanced cancers.

    References: Blood. 2010 Jun 24;115(25):5202-13; Clin Cancer Res. 2011 Dec 15;17(24):7614-24; Mol Cancer Ther. 2012 Mar;11(3):763-74.

    Related CAS #: 1208255-63-3 (sodium); 1028486-06-7 (sodium anhydrous)

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    Molecular Weight (MW)518.92
    FormulaC27H20ClFN4O4
    CAS No.1028486-01-2
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 27 mg/mL (52.0 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)15% Captisol: 5 mg/mL
    Synonyms

    MLN-8237; alisertib; MLN8237; MLN 8237

    Chemical Name: 4-((9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl)amino)-2-methoxybenzoic acid

    SMILES Code: O=C(O)C1=CC=C(NC2=NC=C3C(C4=CC=C(Cl)C=C4C(C5=C(OC)C=CC=C5F)=NC3)=N2)C=C1OC 


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    In Vitro

    In vitro activity: MLN8237 shows >200-fold higher selectivity for Aurora A than the structurally related Aurora B with an IC50 of 396.5 nM, and does not have any significant activity against 205 other kinases. MLN8237 (0.5 μM) treatment inhibits the phosphorylation of Aurora A in MM1.S and OPM1 cells, without affecting the Aurora B mediated histone H3 phosphorylation. MLN8237 significantly inhibits cell proliferation in multiple myeloma (MM) cell lines with IC50 values of 0.003-1.71 μM. MLN8237 displays more potent anti-proliferation activity against primary MM cells and MM cell lines in the presence of BM stroma cells, as well as IL-6 and IGF-1 than against MM cells alone. MLN8237 (0.5 μM) induces 2- to 6-fold increase in G2/M phase in primary MM cells and cell lines, as well as significant apoptosis and senescence, involving the up-regulation of p53, p21 and p27, as well as PARP, caspase 3, and caspase 9 cleavage. In addition, MLN8237 shows strong synergistic anti-MM effect with dexamethasone, as well as additive effect with doxorubicin and bortezomib. MLN8237 (0.5 μM) treatment causes the inhibition of colony formation of FLO-1, OE19, and OE33 esophageal adenocarinoma cell lines, and induces a significant increase in the percentage of polyploid cells, and subsequently an increase in the percentage of cells in the sub-G1 phase, which can be further enhanced in combination with cisplatin (2.5 μM), involving the higher induction of TAp73β, PUMA, NOXA, cleaved caspase-3, and cleaved PARP as compared with a single-agent treatment..


    Kinase Assay: Aurora A radioactive Flashplate enzyme assay is conducted to determine the nature and degree of MLN8237-mediated inhibition in vitro. Recombinant Aurora A is expressed in Sf9 cells and purified with GST affinity chromatography. The peptide substrate for Aurora A is conjugated with biotin (Biotin-GLRRASLG). Aurora A kinase (5 nM) is assayed in 50 mM Hepes (pH 7.5), 10 mM MgCl2, 5 mM DTT, 0.05% Tween 20, 2 μM peptide substrate, 3.3 μCi/mL [γ-33P]ATP at 2 μM, and increasing concentrations of MLN8237 by using Image FlashPlates.


    Cell Assay: Cells are exposed to various concentrations of MLN8237 for 24, 48, and 72 hours. Cells viability is measured using MTT assay, and cell proliferation is measured using 3[H]-thymidine incorporation. For cell cycle analysis, cells are permeabilized by 70% ethanol at -20 °C, and incubated with 50 μg/mL PI and 20 units/mL RNase-A. DNA content is analyzed by flow cytometry using BDFACS-Canto II and FlowJo software. For the detection of apoptosis and senescence, cells are stained with fluorescein isothiocyanate-annexin V and PI. Apoptotic cells are determined by flow cytometric analysis using BDFACS-Canto II and FlowJo software.

    In VivoMLN8237 significantly reduces the tumor burden with tumor growth inhibition (TGI) of 42% and 80% at 15 mg/kg and 30 mg/kg, respectively, and prolongs the survival of mice compared with the control.
    Animal modelSevere combined immune-deficient (SCID) mice inoculated subcutaneously with MM1.S cells
    Formulation & DosageDissolved in 10% 2-hydroxypropyl-β-cyclodextrin/1% sodium bicarbonate; 30 mg/kg;  Oral gavage
    References

    Blood. 2010 Jun 24;115(25):5202-13; Clin Cancer Res. 2011 Dec 15;17(24):7614-24; Mol Cancer Ther. 2012 Mar;11(3):763-74.


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

    Alisertib

    Alisertib

    Alisertib

    MLN8237 and CDDP combination treatment exhibits enhanced anti-tumor activity in vivo. Mol Cancer Ther. 2012 Mar; 11(3): 763–774

    Alisertib

    In vitro cell-based phenotypes consistent with Aurora A and Aurora B inhibition at low and high concentrations, respectively.  2011 Dec 15;17(24):7614-24.

    Alisertib

    Pharmacodynamic activity of alisertib in the HCT-116 xenograft model as determined by increased mitotic index, misaligned chromosomes, and reduced bipolar mitotic spindles.  2011 Dec 15;17(24):7614-24.

    Alisertib

    Broad antitumor activity of alisertib in a diverse set of human tumor xenograft models. A, nude mice bearing subcutaneous HCT-116 tumors were dosed with alisertib orally at 3, 10, and 30 mg/kg once daily for 21 consecutive days. Mean tumor volumes (mm3) ± SEM (n = 10 per group) are shown from the beginning of treatment. B, OCI-LY19 tumors inoculated intravenously were treated with alisertib at 20 mg/kg twice daily, 30 mg/kg once daily, and with rituximab at 10 mg/kg once per week.  2011 Dec 15;17(24):7614-24.


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