MLN-8237 Chemical Properties

Boiling point:

729.1±70.0 °C(Predicted)

Density 

1.43±0.1 g/cm3(Predicted)

storage temp. 

-20°C

solubility 

Soluble in DMSO (up to 5 mg/ml)

form 

solid

pka

4.07±0.10(Predicted)

color 

Off-white

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.

InChIKey

ZLHFILGSQDJULK-UHFFFAOYSA-N

SMILES

C(O)(=O)C1=CC=C(NC2=NC=C3C(=N2)C2=CC=C(Cl)C=C2C(C2=C(OC)C=CC=C2F)=NC3)C=C1OC

MLN-8237 Usage And Synthesis

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.

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.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.

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.

Description

Alisertib (MLN8237, 1028486-01-2) is a highly selective and potent (IC50?= 1 nM) cell permeable inhibitor of Aurora A with off-target binding at GABAA?(IC50?= 490 nM).1?It disrupts the Aurora A-Myc complex leading to Myc degradation2?in Myc amplified neuroblastomas3?and p53-mutant human hepatocellular carcinoma cell4. Alisertib has been found to induce apoptosis and autophagy in breast cancer5?and melanoma6?cells?via?suppression of activation of the p38 MAPK pathway.

Chemical Properties

Off-White Solid

Uses

An Aurora kinase inhibitor, used to treat patients with advanced solid tumors.

Definition

ChEBI: 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid is a benzazepine.

Synthesis

Synthesis of 4-((9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-benzo[c]pyrimido[5,4-d]azepine[5,4-d]-2-yl)amino)-2-methoxybenzoic acid from the compound (CAS:1028486-08-9) and 8-chloro-4-[(dimethylamino)methylene]-1-(2-fluoro-6-methoxyphenyl)-3,4-dihydro-5H-2-benzazepin-5-one -2-yl)amino)-2-methoxybenzoic acid in the following general steps: 1. compound 6 (3.81 kg, 15.5 mol), potassium carbonate (4.3 kg, 31.1 mol), compound 9 (5.27 kg, 14.1 mol) and methanol (63 L) were added to the reactor. 2. the suspension was heated to 50 to 55 °C and stirred continuously for at least 24 hours until a conversion of >96.0% was confirmed by HPLC analysis. 3. Methanol (10 L) and water (37 L) were added while keeping the temperature between 50 and 55 °C. 4. The pH of the mixture was adjusted to 3.0 to 4.0 using a 7% w/w HCl solution (prepared from 7.0 kg of concentrated HCl and 24 L of water) while maintaining the temperature between 50 and 55°C. 5. the suspension was cooled to 20 to 25 °C over a period of at least 1 hour and stirring was continued for at least 60 minutes. 6. The resulting suspension was filtered and the filter cake was washed sequentially with water (2 x 26.3 L) at 50 to 55°C and methanol (2 x 10 L) at 20 to 25°C. 7. the wet filter cake was vacuum dried at 45 to 50 °C to give 5.85 kg (80% yield) of the target product formula (II). Product characterization data: 3/4 NMR (300 MHz, DMSO-d6) δ 12.07 (s, 1H), 10.22 (s, 1H), 8.72 (s, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.95 (s, 1H), 7.80 (dd, J = 2.4, 8.9 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H) , 7.39 (m, 3H), 7.21 (s, 1H), 6.89 (s, 2H), 3.82 (s, 6H); MS (ESI) m/z 517.2 (M-H+, 45%).

target

Aurora A

References

[1] TODD B. SELLS*. MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors[J]. ACS Medicinal Chemistry Letters, 2015, 6 6: 630-634. DOI:10.1021/ml500409n
[2] MARK W RICHARDS. Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors.[J]. Journal of Electroanalytical Chemistry, 2016, 921: 13726-13731. DOI:10.1073/pnas.1610626113
[3] MARKUS BROCKMANN. Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma.[J]. Cancer Cell, 2013, 24 1: 75-89. DOI:10.1016/j.ccr.2013.05.005
[4] DANIEL DAUCH. A MYC–aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer[J]. Nature Medicine, 2016, 22 7: 744-753. DOI:10.1038/nm.4107
[5] JIN-PING LI. The investigational Aurora kinase A inhibitor alisertib (MLN8237) induces cell cycle G2/M arrest, apoptosis, and autophagy via p38 MAPK and Akt/mTOR signaling pathways in human breast cancer cells.[J]. Drug Design, Development and Therapy, 2015, 9: 1627-1652. DOI:10.2147/dddt.s75378
[6] YUAN-YUAN SHANG. Alisertib promotes apoptosis and autophagy in melanoma through p38 MAPK-mediated aurora a signaling.[J]. Oncotarget, 2017, 8 63: 107076-107088. DOI:10.18632/oncotarget.22328

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