Alisertib (MLN8237)

Catalog No.S1133

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

Cited by 46 publications:

10 customer reviews :

Quality Control & MSDS

Related Compound Libraries

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

Aurora Kinase Inhibitors with Unique Features

Product Information

  • Compare Aurora Kinase Inhibitors
    Compare Aurora Kinase Products
  • Research Area
  • Inhibition Profile
  • 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]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
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Kasumi-1NVPZdZZMT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=M1vCZ|ExKM7:TR?=MlXrPVYhcA>?NULMW3BuUUN3ME2wMlExOyEQvF2=NX;uZYxmOjBzMEizN|g>
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... Click to View More Cell Line Experimental Data

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 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02812056 Not yet recruiting Malignant Neoplasms of Digestive Organs|Malignant Neoplasms of Female Genital Organs|Malignant Neoplasms of Lip Oral Cavity and Pharynx|Malignant N  ...more Malignant Neoplasms of Digestive Organs|Malignant Neoplasms of Female Genital Organs|Malignant Neoplasms of Lip Oral Cavity and Pharynx|Malignant Neoplasms of Male Genital Organs M.D. Anderson Cancer Center|Millennium Pharmaceuticals, Inc. September 2016 Phase 1
NCT02700022 Recruiting Diffuse Large B-cell Lymphoma|Follicular Lymphoma|Burkitt Lymphoma UNC Lineberger Comprehensive Cancer Center|Millennium Pha  ...more UNC Lineberger Comprehensive Cancer Center|Millennium Pharmaceuticals, Inc. July 2016 Phase 1
NCT02719691 Recruiting Metastatic Breast Cancer|Solid Tumors University of Colorado, Denver May 2016 Phase 1
NCT02530619 Recruiting Acute Megakaryoblastic Leukemia|Myelofibrosis|Primary Myelofibrosis Northwestern University|The Leukemia and Lymphoma Society  ...more Northwestern University|The Leukemia and Lymphoma Society|Millennium Pharmaceuticals, Inc.|National Cancer Institute (NCI) October 2015 --
NCT02560025 Not yet recruiting Acute Myeloid Leukemia Massachusetts General Hospital|Takeda October 2015 Phase 2

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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
2 years -80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 27 mg/mL (52.03 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
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-

Frequently Asked Questions

  • Question 1
    What is the suggested formulation of this compound for mouse injection(i.p.)?

    Answer: It can be dissolved in 6% DMSO/50% PEG 300/5% Tween 80/ddH2O at 10 mg/ml as a clear solution.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Tel: +1-832-582-8158 Ext:3

If you have any other enquiries, please leave a message.

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