Alisertib (MLN8237)

SKU: orb1305944

Description

Alisertib (MLN8237) is a potent and selective oral Aurora A kinase inhibitor (IC50=1.2 nM). It exhibits antitumor activity by inducing cell cycle arrest, apoptosis, and autophagy, as demonstrated in both in vitro cellular assays and in vivo xenograft models across various cancer research fields.

Research Area

Cell Biology

Key Properties

• CAS Number: 1028486-01-2
• MW: 518.9
• Purity: >98%
• Formula: C₂₇H₂₀ClFN₄O₄
• SMILES: COc1cc(Nc2ncc3CN=C(c4cc(Cl)ccc4-c3n2)c2c(F)cccc2OC)ccc1C(O)=O
• Target: Kinase
• Solubility: Soluble in DMSO (up to 5 mg/ml)

Bioactivity

• Target IC50:
  MKN45 cells:93 nM|Aurora A:1.2 nM (cell free)|HL-60 cells:74 nM|HT29 cells:330 nM|PC14 cells:170 nM|MV-4-11 cells:1.2 nM|Sf9 cells:1 nM|LC-2-ad cells:77 nM|Aurora B:396.5 nM|NCI-H358 cells:100 nM|MIAPaCa2 cells:130 nM|MRC5 cells:> 10000 nM|HCT116 cells:1.5 μM|LU-99A cells:62 nM
• In Vivo:
  Tumor burden was significantly reduced and overall survival was significantly increased in animals treated with 30 mg/kg MLN8237 for 21 days. Induction of apoptosis and cell death by MLN8237 were confirmed in tumor cells excised from treated animals by TdT-mediated dUTP nick end labeling assay . Alisertib produced a dose-dependent decrease in bipolar and aligned chromosomes in the HCT-116 xenograft model. Alisertib produced tumor growth inhibition in solid tumor xenograft models and regressions in in vivo lymphoma models. In addition, a dose of alisertib that caused tumor stasis, as measured by volume, resulted in a decrease in FLT uptake . Nude mice bearing human tumor xenografts treated with a single oral dose of alisertib (20 mg/kg) displayed a phenotype consistent with inhibition of Aurora A .
• In Vitro:
  Treatment of cultured MM cells with Alisertib (MLN8237) results in mitotic spindle abnormalities, mitotic accumulation, as well as inhibition of cell proliferation through apoptosis and senescence. In addition, MLN8237 up-regulates p53 and tumor suppressor genes p21 and p27. Combining MLN8237 with dexamethasone, doxorubicin, or bortezomib induces synergistic/additive anti-MM activity in vitro . Alisertib inhibited AAK over ABK with a selectivity of more than 200-fold in cells. Alisertib inhibited proliferation of human tumor cell lines in vitro . A T217D/W277E double mutant exhibits superior levels of resistance to MLN8237, with the I50 value increasing approximately 20-fold from 30 to 650 nM in the presence of TPX2 .
• Cell Research:
  HCT-116 colorectal carcinoma cells were plated on 6-well dishes (2 × 10^5 per well) and propagated in McCoy's 5A media supplemented with 10% FBS. After 18 hours, alisertib at a final concentration of 0.050, 0.250, or 1.000 μmol/L was added, and the cells were grown for an additional 24 hours. Cells treated with dimethyl sulfoxide (DMSO; 0.2%) served as the untreated vehicle control. The cells were harvested with trypsin EDTA 1×, washed once with PBS, fixed in 70% ethanol, and stored at 4°C for 1 hour. The cells were resuspended in propidium iodide (1:40) and RNAse A (1:5,000) in PBS for 30 minutes at 4°C. Cell-cycle distributions were determined by measuring DNA content using flow cytometry, and samples were analyzed using Winlist 5.0 software .
• Animal Research:
  Mice were irradiated (200 cGy), and then 5 × 106 MM1.S cells were inoculated subcutaneously in the right flank. When tumor growth was measurable (～ 2 weeks after the injection), mice were assigned into 4 groups (10 mice each) receiving vehicle orally (100 μL of 10% 2-hydroxypropyl-β-cyclodextrin/1% sodium bicarbonate) or MLN8237 (7.5 mg/kg, 15 mg/kg, and 30 mg/kg in a final formulation in 10% 2-hydroxypropyl-β-cyclodextrin/1% sodium bicarbonate) for 21 consecutive days. The maximal tolerated dose of MLN8237 in most mouse strains (continuous dosing for 21 days) is approximately 20 mg/kg twice a day (40 mg/kg per day). Tumor volumes were measured by a Vernier caliper every alternate day and calculated using the following formula: length × width2 × 0.5. Tumor growth inhibition (TGI) was calculated using the formula (Δcontrol average volume Δtreated average volume) × 100/(Δcontrol average volume). Mice were killed at the end of the treatment, 2 hours after the last treatment, or when tumor reached 2 cm^3; tumors were immediately collected from mice and evaluated for induction of apoptosis and cell death by TdT-mediated dUTP nick end labeling (TUNEL) assay .

Storage & Handling

• Storage: -20°C
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

MLN8237

Compound Identifiers

PubChem CID

24771867