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).1It disrupts the Aurora A-Myc complex leading to Myc degradation2in Myc amplified neuroblastomas3and p53-mutant human hepatocellular carcinoma cell4. Alisertib has been found to induce apoptosis and autophagy in breast cancer5and melanoma6cellsviasuppression 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%).
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
![(1E,4E)-8-chloro-4-((diMethylaMino)Methylene)-1-(2-fluoro-6-Methoxyphenyl)-3,4-dihydrobenzo[c]azepin-5-one](/CAS/GIF/869367-33-9.gif)
