Antibodies
Alisertib (MLN8237)
- 貨號 Cat. No.
- S1133
- 規格 Size
- 5~200mg
- 品牌 Brand
- Selleckchem
Description
Alisertib (MLN8237)
Alisertib (MLN8237) is a selective Aurora A inhibitor with IC50 of 1.2 nM. It has >200-fold higher selectivity for Aurora A than Aurora B. Phase 3.
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Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw
Biological Activity
| Description | Alisertib (MLN8237) is a selective Aurora A inhibitor with IC50 of 1.2 nM. It has >200-fold higher selectivity for Aurora A than Aurora B. Phase 3. | |||||
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| Targets | Aurora A | |||||
| IC50 | 1.2 nM [1] | |||||
| 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. |
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Cell Assay: [2]
| Cell lines | MM1.S, MM.1R, LR5, RPMI 8226, DOX40, OPM1, OPM2, INA6, and U266 |
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| 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 |
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| Dosages | ~30 mg/kg/day |
| Administration | Orally |
| Solubility | 15% Captisol, 30 mg/mL |
References
Clinical Trial Information( data from http://clinicaltrials.gov)
| NCT Number | Recruitment | Conditions | Sponsor /Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT01779843 | Recruiting | Acute Myelogenous Leukemia | Massachusetts General Hospital | 2013-04 | Phase 1 |
| NCT01812005 | Recruiting | Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue|Nodal Marginal Zone B-cell Lymphoma|Recurrent Adult Burkitt Lymphoma|Recurrent Adult Diffuse Large Cell Lymphoma etc. | Ohio State University Comprehensive Cancer Center|Kristie Blum|Millennium Pharmaceuticals, Inc. | 2013-05 | Phase 2 |
| NCT01848067 | Not yet recruiting | Adenocarcinoma of the Prostate|Hormone-resistant Prostate Cancer|Recurrent Prostate Cancer|Stage IV Prostate Cancer | Thomas Jefferson University|Millennium: The Takeda Oncology Company | 2013-05 | Phase 1|Phase 2 |
| NCT01613261 | Not yet recruiting | Advanced Nonhematologic Malignancies | Millennium Pharmaceuticals, Inc. | 2013-06 | Phase 1 |
| NCT01844583 | Not yet recruiting | Solid Tumors|Lymphoma | Millennium Pharmaceuticals, Inc. | 2013-06 | Phase 1 |
Chemical Information
Download Alisertib (MLN8237) SDF
| Molecular Weight (MW) | 518.92 |
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| Formula | C27H20ClFN4O4 |
| CAS No. | 1028486-01-2 |
| Storage | 3 years -20℃Powder |
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| 6 months-80℃in DMSO | |
| Syonnyms | N/A |
| Solubility (25°C) * | In vitro | DMSO | 27 mg/mL (52 mM) |
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| 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- |
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Customer Reviews (8)
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| 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. |
Product Citations (19)
Regulation of Embryonic and Induced Pluripotency by Aurora Kinase-p53 Signaling. [Lee DF, et al. Cell Stem Cell 2012;11(2):179-94]
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]
Early adipogenesis is regulated through USP7-mediated deubiquitination of the histoneacetyltransferase TIP60. [Gao Y, et al. Nat Commun 2013;4:2656]
