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Alisertib (MLN8237)

Alisertib (MLN8237)

Hersteller	Selleckchem
Kategorie	Oncology Food Safety Drugs Neuroscience Neural Lineage Markers Metabolism Diabetes Glucose Homeostasis Targets for Rodent Neurosciences Inhibitors & Compound Libraries Small Molecules By Organ Lung Cancer Bladder Cancer Colorectal Cancer Breast Cancer Lymphatic System Cancer Uterine, Ovarian & Cervical Cancer Oligodendrocyte Markers
Typ	Inhibitors
Specific against	other
Menge	10 mg
ArtNr	S1133-10
CAS-Nr.	1028486-01-2
eClass 6.1	30220300
eClass 9.0	32160605
Lieferbar
Administration	Orally
Animal Models	Severe combined immune-deficient (SCID) mice inoculated subcutaneously with MM1.S cells
Cell lines	MM1.S, MM.1R, LR5, RPMI 8226, DOX40, OPM1, OPM2, INA6, and U266
Chemical Name	Benzoic acid, 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5, 4-d][2]benzazepin-2-yl]amino]-2-methoxy-
Clinical Trials	A Phase II study of MLN8237 for treatment of patients with ovarian, fallopian tube, or peritoneal carcinoma has been completed.
Concentrations	Dissolved in DMSO, final concentrations ca.10 uM
Description	MLN8237 (Alisertib) is a selective Aurora A inhibitor with IC50 of 1.2 nM.
Dosages	ca.30 mg/kg/day
Features	First orally available inhibitor of Aurora A
Formulation	Formulated in 10% 2-hydroxypropyl-beta-cyclodextrin/1% sodium bicarbonate
IC50	1.2 nM [1], 1.2 nM [1], 1.2 nM [1], 1.2 nM [1], 1.2 nM [1], 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 uM) 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 uM. 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 uM) 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 uM) 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 uM), involving the higher induction of TAp73beta, 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]
Incubation Time	24, 48, and 72 hours
Kinase Assay	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 uM peptide substrate, 3.3 uCi/mL [gamma-33P]ATP at 2 uM, and increasing concentrations of MLN8237 by using Image FlashPlates.
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 ug/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.
Molecular Weight (MW)	518, 92
Picture ChemicalStructure Description	MLN8237 (Alisertib) Chemical Structure
Picture Description 1	Data from [ACS Chem Biol , 2010, 5, 563-576], MLN8237 (Alisertib)purchased from Selleck, Inhibition of Aurora A (12.5 nM) by MLN8054 or MLN8237 was assessed in duplicate radiometric assays containing 100 M [-32P] ATP and quantified by p81 phosphocellulose assay and scintillation counting. Kinase activity is reported as a percentage of control calculated from duplicate incubations containing 2.5% (v/v) DMSO. IC50 values represent the mean SEM calculated from two independent experiments.
Picture Description 2	Data from [ACS Chem Biol , 2010, 5, 563-576], MLN8237 (Alisertib)purchased from Selleck, The effects of T217D and T217N Aurora A mutations were directly compared to WT Aurora A-expressing cells. Each well was treated with either DMSO or 500 nM MLN8054 (E), or 30 nM MLN8237 (F) on day one of the experiment and cells were cultured for 8 days, at which point they were fixed. For all colony assays, an area encompassing 90 % of the colonies per dish is shown. Similar results were seen in two independent duplicate experiments.
Solubility (25C)	DMSO 3 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL
Storage	2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO

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