| Identification | Back Directory | [Name]
Alisertib (MLN8237) | [CAS]
1028486-01-2 | [Synonyms]
MLN-8237
Alisertib
Alisertib (MLN8237)
MLN8237 (Alisertib)
MLN 8237 (Contain 10% DMSO)
alisertib (auroura A kinase inhibitor)
4-((9-Chloro-7-(2-fluoro-6-methoxyphenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-yl)amino)-2-methoxy
4-[[9-Chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid
4-((9-chloro-7-(2-fluoro-6-Methoxyphenyl)-5H-benzo[c]pyriMido[4,5-e]azepin-2-yl)aMino)-2-Methoxybenzoic acid
Benzoic acid, 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxy-
MLN-8237 4-[[9-Chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid | [EINECS(EC#)]
1592732-453-0 | [Molecular Formula]
C27H20ClFN4O4 | [MDL Number]
MFCD16621243 | [MOL File]
1028486-01-2.mol | [Molecular Weight]
518.924 |
| Chemical Properties | Back Directory | [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 |
| Hazard Information | Back Directory | [Chemical Properties]
Off-White Solid | [Usage]
An Aurora kinase inhibitor, used to treat patients with advanced solid tumors. | [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) Sells?et al.?(2015),?MLN8054 and Alisertib (MLN8237):Discovery of Selective Oral Aurora A Inhibitors; ACS Med. Chem. Lett.?6?630
2) Richards?et al.?(2016),?Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors; Proc. Natl. Acad. Sci. USA?113?13726
3) Brockmann?et al.?(2013),?Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma; Cancer Cell?24?75
4) Dauch?et al.?(2016),?A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer; Nat. Med.?22?744
5) Li?et al.?(2015),?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; Drug Des. Devel. Ther.?16?1627
6) Shang?et al.?(2017),?Alisertib promotes apoptosis and autophagy in melanoma through p38 MAPK-mediated aurora a signaling; Oncotarget?8?107076 |
| Questions And Answer | Back Directory | [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. |
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