Home > Compound List > Product Information
MLN8237_Molecular_structure_CAS_1028486-01-2)
Click picture or here to close

MLN8237

Catalog No. S1133 Name Selleck Chemicals
CAS Number 1028486-01-2 Website http://www.selleckchem.com
M. F. C27H20ClFN4O4 Telephone (877) 796-6397
M. W. 518.9235032 Fax (832) 582-8590
Purity Email sales@selleckchem.com
Storage -20°C Chembase ID: 72530

SYNONYMS

IUPAC name
4-{[13-chloro-10-(2-fluoro-6-methoxyphenyl)-3,5,9-triazatricyclo[9.4.0.0^{2,7}]pentadeca-1(11),2(7),3,5,9,12,14-heptaen-4-yl]amino}-2-methoxybenzoic acid
IUPAC Traditional name
4-{[13-chloro-10-(2-fluoro-6-methoxyphenyl)-3,5,9-triazatricyclo[9.4.0.0^{2,7}]pentadeca-1(11),2(7),3,5,9,12,14-heptaen-4-yl]amino}-2-methoxybenzoic acid

DATABASE IDS

CAS Number 1028486-01-2

PROPERTIES

Target Aurora
Salt Data Free Base
Solubility DMSO
Storage Condition -20°C

DETAILS

Description (English)
Research Area
Description on-Hodgkin's lymphoma,cancer, Solid tumours
Biological Activity
Description MLN8237 (Alisertib) is a selective Aurora A inhibitor with IC50 of 1.2 nM.
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]
Clinical Trials A Phase II study of MLN8237 for treatment of patients with ovarian, fallopian tube, or peritoneal carcinoma has been completed.
Features First orally available inhibitor of Aurora A
Combination Therapy
Description MLN8237 (30 mg/kg) in combination with cisplatin (2 mg/kg) displays an enhanced anti-tumor activity against FLO-1xenografts, as compared with single-agent treatments, correlating with the suppressed Ki-67 expression, enhanced nuclear p73 protein and cleaved caspase 3 expression. [3]
Protocol
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
Methods 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
Doses ~30 mg/kg/day
Administration Orally
References
[1] Manfredi MG, et al. Clin Cancer Res, 2011, 17(24), 7614-7624.
[2] Görgün G, et al. Blood, 2010, 115(25), 5202-5213.
[3] Sehdev V, et al. Mol Cancer Ther, 2012, 11(3), 763-774.