Alisertib (MLN8237)

Alisertib (MLN8237) is a selective Aurora A inhibitor with IC50 of 1.2 nM in a cell-free assay. It has >200-fold higher selectivity for Aurora A than Aurora B. Phase 3.

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Alisertib (MLN8237) Chemical Structure

Alisertib (MLN8237) Chemical Structure
Molecular Weight: 518.92

Validation & Quality Control

Product Use Citation(44)

Customer Product Validation(10)

Quality Control & MSDS

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Alisertib (MLN8237) is available in the following compound libraries:

Aurora Kinase Inhibitors with Unique Features

Product Information

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  • Research Area
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  • Combination Therapy
    Combination Therapy

Product Description

Biological Activity

Description Alisertib (MLN8237) is a selective Aurora A inhibitor with IC50 of 1.2 nM in a cell-free assay. It has >200-fold higher selectivity for Aurora A than Aurora B. Phase 3.
Targets Aurora A [1]
(Cell-free assay)
Aurora B [1]
(Cell-free assay)
IC50 1.2 nM 396.5 nM
In vitro 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 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]
Features First orally available inhibitor of Aurora A.

Protocol(Only for Reference)

Kinase Assay: [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.

Cell Assay: [2]

Cell lines MM1.S, MM.1R, LR5, RPMI 8226, DOX40, OPM1, OPM2, INA6, and U266
Concentrations Dissolved in DMSO, final concentrations ~10 μM
Incubation Time 24, 48, and 72 hours
Method 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.

Animal Study: [2]

Animal Models Severe combined immune-deficient (SCID) mice inoculated subcutaneously with MM1.S cells
Formulation Formulated in 10% 2-hydroxypropyl-β-cyclodextrin/1% sodium bicarbonate
Dosages ~30 mg/kg/day
Administration Orally

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Manfredi MG, et al. Clin Cancer Res, 2011, 17(24), 7614-7624.

[2] G?rgün G, et al. Blood, 2010, 115(25), 5202-521

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2015-06-27)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02319018 Not yet recruiting Malignant Digestive System Neoplasm National Cancer Institute (NCI) September 2015 Phase 1
NCT02293005 Recruiting Lung Cancer|Mesothelioma M.D. Anderson Cancer Center|Millennium Pharmaceuticals, Inc. May 2015 Phase 2
NCT02367352 Recruiting Advanced Solid Tumors|Ovarian Cancer|Small Cell Lung Cancer Millennium Pharmaceuticals, Inc. March 2015 Phase 1
NCT02327169 Recruiting Advanced Nonhematologic Malignancies Millennium Pharmaceuticals, Inc. February 2015 Phase 1
NCT02186509 Recruiting Adult Anaplastic Astrocytoma|Adult Anaplastic Ependymoma|Adult Anaplastic Oligodendroglioma|Adult Brain Stem Glioma|Adult Diffuse Astrocytoma|Adult  ...more Adult Anaplastic Astrocytoma|Adult Anaplastic Ependymoma|Adult Anaplastic Oligodendroglioma|Adult Brain Stem Glioma|Adult Diffuse Astrocytoma|Adult Giant Cell Glioblastoma|Adult Glioblastoma|Adult Gliosarcoma|Adult Mixed Glioma|Adult Oligodendroglioma|Adult Pilocytic Astrocytoma|Adult Pineal Gland Astrocytoma|Adult Subependymal Giant Cell Astrocytoma|Recurrent Adult Brain Tumor Thomas Jefferson University|Millennium Pharmaceuticals, Inc. January 2015 Phase 1

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Chemical Information

Download Alisertib (MLN8237) SDF
Molecular Weight (MW) 518.92
Formula

C27H20ClFN4O4

CAS No. 1028486-01-2
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 27 mg/mL (52.03 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 15% Captisol 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name Benzoic acid, 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxy-

Customer Product Validation (10)


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Rating
Source Cell Stem Cell 2012 11, 179-94. Alisertib (MLN8237) purchased from Selleck
Method qPCR
Cell Lines CCE cells
Concentrations 1 uM
Incubation Time 48 h
Results Treatment with the Aurka-specific chemical inhibitor MLN8237 suppressed pluripotency TF expression and decreased fluorescence in the NG4 Nanog-GFP reporter line.

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Rating
Source EMBO J 2012 30, 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.

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Rating
Source J Cell Biol 2010 191, 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).

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Rating
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.

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Rating
Source EMBO Mol Med 2013 5(1), 149-66. Alisertib (MLN8237) purchased from Selleck
Method Immunofluorescence co-staining
Cell Lines Hs294T xenograft
Concentrations 30 mg/kg
Incubation Time 28 days
Results To extend its findings in vivo, we examined senescence (SA-b-Gal staining), DNA damage (53BP1), NF-kB activity (IkB-a) and the SASP (IL-6) in an Hs294T xenograft tumour after MLN 8237 treatment. Tumour tissues treated with MLN8237 were b-galactosidase-positive (blue), 53BP1 (red) was increased.

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Rating
Source Oncogene 2014 33, 3550-60. 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.

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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.

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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

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Rating
Source J Biol Chem 2012 287, 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.

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Rating
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.

Product Use Citation (44)

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