Alisertib (MLN8237)

Alisertib (MLN8237)は、1.2nMのIC50による選択的なオーロラA阻害剤です。

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Alisertib (MLN8237) 化学構造
分子量: 518.92



Quality Control & MSDS


  • Combination Therapy
  • Compare Aurora Kinase Inhibitors
    Aurora Kinase阻害剤を比較
  • 研究分野



情報 Alisertib (MLN8237)は、1.2nMのIC50による選択的なオーロラA阻害剤です。
目標 Aurora A
IC50 1.2 nM [1]
In vitro試験 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. [1] 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. [2] 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. [3]
In vivo試験 MLN8237 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. [2]
臨床試験 A Phase II study of MLN8237 for treatment of patients with ovarian, fallopian tube, or peritoneal carcinoma has been completed.
特集 First orally available inhibitor of Aurora A.

推薦された実験操作 (公開の文献だけ)

キナーゼアッセイ: [1]

Aurora A radioactive Flashplate enzyme 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.

細胞アッセイ: [2]

細胞系 MM1.S, MM.1R, LR5, RPMI 8226, DOX40, OPM1, OPM2, INA6, and U266
濃度 Dissolved in DMSO, final concentrations ~10 μM
処理時間 24, 48, and 72 hours
方法 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.

動物実験: [2]

動物モデル Severe combined immune-deficient (SCID) mice inoculated subcutaneously with MM1.S cells
製剤 Formulated in 10% 2-hydroxypropyl-β-cyclodextrin/1% sodium bicarbonate
投薬量 ~30 mg/kg/day
管理 Orally



Download Alisertib (MLN8237) SDF
分子量 518.92


CAS No. 1028486-01-2
別名 N/A
溶解度 (25°C)
  • DMSO 27 mg/mL
  • 水 <1 mg/mL
  • エタノール <1 mg/mL
保管 2年 -20°C
6月-80°Cin DMSO
化学名 Benzoic acid, 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxy-


カスタマーレビュー (8)

Click to enlarge
Source Oncogene. 2013 Aug 19. Alisertib (MLN8237) purchased from Selleck
Method Western blot, time-lapse microscopy, flow cytometry
Cell Lines HeLa cells
Concentrations 6-1000 nM
Incubation Time 2 h,8 h,24 h,48 h
Results Alisertib inhibits AURKA and AURKB in a concentration-dependent manner.

Click to enlarge
Source J Cell Biol, 2010, 191(7), 1315-32. Alisertib (MLN8237) purchased from Selleck
Method DAPI staining
Cell Lines HeLa cells
Concentrations 10/20 nM
Incubation Time 15 min/24 h
Results Depletion of PPP6C resulted in a twofold increase in the pT288 form of Aurora A at prometaphase and metaphase spindles compared with control cells, and addition of 10 nM MLN8237 reversed this increase (Fig. A). Importantly, this partial Aurora A inhibition with 10 nM MLN8237 also reduced the micronucleation seen in PPP6C-depleted cells from 40 to 5% (Fig. B).

Click to enlarge
Source J Biol Chem, 2012, 287(33), 27670-81. Alisertib (MLN8237) purchased from Selleck
Method Immunofluorescence Microscopy
Cell Lines HeLa cells
Concentrations 100 nM
Incubation Time 2 h
Results The fluorescence intensity of the pT210 signal in the spindle poles was markedly decreasedin Fry-depleted cells. Exposure to MLN8237, a specific inhibitor of Aurora A, also abrogated the pT210 signal in the spindle poles.

Click to enlarge
Source Mol Cancer, 2011, 10, 131. Alisertib (MLN8237) purchased from Selleck
Method immunofluorescence
Cell Lines U2OS cells
Concentrations 20/50 nM
Incubation Time 4 h
Results MLN8237 treatment lasted 4 hours and yielded the induction of spindle abnormalities. Spindles with multiple poles represented 15-20 % of all PM/Ms in M LN8237-treated cultures, comparable to the occurrence in Aurora-Ai cultures. When MON was added, Eg5 was inhibited, and the generation of spindles with fragmented poles in MLN8237-treated cultures was abolished, with a parallel increase in mono polar figures.

Click to enlarge
Source EMBO J, 2011, 30(5), 906-19. Alisertib (MLN8237) purchased from Selleck
Method immunofluorescence
Cell Lines HEK293 cells
Concentrations 0.3 μM
Incubation Time 40 min
Results Incubation of cells with the Aurora-A kinase inhibitor MLN8237 (0.3 μM) induced a change in the localisation of endogenous TACC3 and clathrin from the mitotic spindle to the cytoplasm.

Click to enlarge
Source ACS Chem Biol , 2010, 5, 563-576. Alisertib (MLN8237) purchased from Selleck
Method Duplicate radiometric assays
Cell Lines
Concentrations 0.1-1000 nM
Incubation Time
Results These clinical stage compounds MLN8237 and MLN8254, which exhibit subtly different chemistry, display similar potency towards Aurora A in vitro.

Click to enlarge
Source ACS Chem Biol , 2010, 5, 563-576. Alisertib (MLN8237) purchased from Selleck
Method Colony assays
Cell Lines WT Aurora A-expressing cells
Concentrations 30 nM
Incubation Time 8 d
Results We find that a T217D/W277E double mutant does not induce cellular resistance to MLN8054 or MLN8237 in cells

Click to enlarge
Source EMBO reports , 2010, 11, 977-984. Alisertib (MLN8237) purchased from Selleck
Method Immunoprecipitation, MS/MS analysis
Cell Lines HeLa cells
Concentrations 0.5 µM
Incubation Time 1 h
Results This phosphopeptide was absent in interphase cells and strongly reduced in mitotic cells treated with the inhibitor.

製品表彰状 (19)

  • Regulation of Embryonic and Induced Pluripotency by Aurora Kinase-p53 Signaling. [Lee DF, et al. Cell Stem Cell 2012;11(2):179-94]

    PubMed: 22862944
  • Protein phosphatase 6 regulates mitotic spindle formation by controlling the T-loop phosphorylation state of Aurora A bound to its activator TPX2. [Zeng K, et al. J Cell Biol 2010;191(7):1315-32]

    PubMed: 21187329
  • Early adipogenesis is regulated through USP7-mediated deubiquitination of the histoneacetyltransferase TIP60. [Gao Y, et al. Nat Commun 2013;4:2656]

    PubMed: 24141283
  • A TACC3/ch-TOG/clathrin complex stabilises kinetochore fibres by inter-microtubule bridging. [Booth DG, et al. EMBO J 2011;30(5):906-19]

    PubMed: 21297582
  • Targeting Sonic Hedgehog-Associated Medulloblastoma through Inhibition of Aurora and Polo-like Kinases. [Markant SL, et al. Cancer Res 2013;73(20):6310-22]

    PubMed: 24067506
  • Uncovering new substrates for Aurora A kinase. [Sardon T, et al. EMBO reports 2010;11(12):977-84]

    PubMed: 21072059
  • PCM1 Recruits Plk1 to Pericentriolar Matrix to Promote Primary Cilia Disassembly before Mitotic Entry. [Wang G, et al. J Cell Sci 2013;126(Pt 6):1355-65]

    PubMed: 23345402
  • Drug-resistant Aurora A mutants for cellular target validation of the small molecule kinase inhibitors MLN8054 and MLN8237. [Sloane D, et al. ACS Chem Biol 2010;5(6):563-76]

    PubMed: 20426425
  • A functional cooperativity between Aurora A kinase and LIM kinase1: Implication in the mitotic process. [Ritchey L, et al. Cell Cycle 2012;11(2):296-309]

    PubMed: 22214762
  • Tetraploidization increases sensitivity to Aurora B kinase inhibition. [Marxer M, et al. Cell Cycle 2012;11(13):2567-77]

    PubMed: 22722494
  • Aurora-A inactivation causes mitotic spindle pole fragmentation by unbalancing microtubule-generated forces. [Asteriti IA, et al. Mol Cancer 2011;10:131]

    PubMed: 22011530
  • The centrosomal adaptor TACC3 and the microtubule polymerase chTOG interact via defined C-terminal subdomains in an Aurora-A kinase independent manner. [Thakur HC, et al. J Biol Chem 2013;289(1):74-88]

    PubMed: 24273164
  • Furry Protein Promotes Aurora A-mediated Polo-like Kinase 1 Activation. [Ikeda M, et al. J Biol Chem 2012;287(33):27670-81]

    PubMed: 22753416
  • Co-treatment with vorinostat synergistically enhances activity of Aurora kinase inhibitor against human breast cancer cells. [Fiskus W, et al. Breast Cancer Res Treat 2012;135(2):433-44]

    PubMed: 22825030
  • The Cytoskeletal Protein RHAMM and ERK1/2 Activity Maintain the Pluripotency of Murine Embryonic Stem Cells. [Jiang J, et al. PLoS One 2013;8(9):e73548]

    PubMed: 24019927
  • Evolution of Resistance to Aurora Kinase B Inhibitors in Leukaemia Cells. [Failes TW, et al. PLoS One 2012;7(2):e30734]

    PubMed: 22359551
  • Targeting Aurora kinase A suppresses the growth of human oral squamous cell carcinoma cells in vitro and in vivo. [Tanaka H, et al. Oral Oncol 2013;49(6):551-9]

    PubMed: 23481312
  • Emerging drugs for high-grade osteosarcoma. [Hattinger CM, et al. Expert Opin Emerg Drugs 2010;15(4):615-34]

    PubMed: 20690888
  • CDKN1A-mediated Responsiveness of MLL-AF4-positive Acute Lymphoblastic Leukemia to Aurora Kinase-A Inhibitors. [Chen YP ,et al. Int J Cancer 2013;10.1002/ijc.28708]

    PubMed: 24382688



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