1028486-01-2

Basic information

• Product Name: MLN-8237
• Synonyms: 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;alisertib (auroura A kinase inhibitor);Fluorocyclopentenylcytosine;4-((9-Chloro-7-(2-fluoro-6-methoxyphenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-yl)amino)-2-meth;MLN-823;4-[[9-Chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid;MLN-8237
• CAS NO: 1028486-01-2
• Molecular Formula: C₂₇H₂₀ClFN₄O₄
• Molecular Weight: 518.9235032
• EINECS: 1592732-453-0
• Product Categories: Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Inhibitor;API
• Mol File: 1028486-01-2.mol
• Article Data: 3

Chemical Properties

• Boiling Point: 729.134 °C at 760 mmHg
• Flash Point: 394.766 °C
• Appearance: /
• Density: 1.438 g/cm³
• Storage Temp.: -20°C
• Solubility: Soluble in DMSO (up to 5 mg/ml)
• PKA: 4.07±0.10(Predicted)
• 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.
• CAS DataBase Reference: MLN-8237(CAS DataBase Reference)
• NIST Chemistry Reference: MLN-8237(1028486-01-2)
• EPA Substance Registry System: MLN-8237(1028486-01-2)

Safety Data

• Hazardous Substances Data: 1028486-01-2(Hazardous Substances Data)

Usage

Description

MLN-8237, also known as Alisertib, is a selective Aurora A inhibitor with high potency and selectivity, characterized by an IC50 of 1.2 nM in a cell-free assay and more than 200-fold higher selectivity for Aurora A than Aurora B. It is an off-white solid that disrupts the Aurora A-Myc complex, leading to Myc degradation in Myc amplified neuroblastomas and p53-mutant human hepatocellular carcinoma cells. Additionally, it induces apoptosis and autophagy in breast cancer and melanoma cells via suppression of the p38 MAPK pathway activation.

Uses

Used in Oncology:
MLN-8237 is used as an anticancer agent for the treatment of patients with advanced solid tumors. It targets Aurora A, a key regulator of cell division, and has been found to induce apoptosis and autophagy in various cancer types, including breast cancer and melanoma.
Used in Drug Development:
MLN-8237 is used as a research tool in the development of new cancer therapies. Its high selectivity and potency make it a valuable compound for studying the role of Aurora A in cancer progression and for identifying potential synergistic effects with other drugs.
Used in Preclinical and Clinical Research:
MLN-8237 is used in preclinical and clinical research to evaluate its safety, efficacy, and potential side effects in treating various types of cancer. It has reached Phase 3 in clinical trials, indicating its potential as a viable treatment option for cancer patients.

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.

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

InChI:InChI=1S/C27H20ClFN4O4/c1-36-21-5-3-4-20(29)23(21)25-19-10-15(28)6-8-17(19)24-14(12-30-25)13-31-27(33-24)32-16-7-9-18(26(34)35)22(11-16)37-2/h3-11,13H,12H2,1-2H3,(H,34,35)(H,31,32,33)

Upstream product

• 869367-01-1 8-chloro-1-(2-fluoro-6-methoxyphenyl)-3,4-dihydrobenzo[c]azepin-5-one 
• 1332307-86-4 methyl 4-{[ammo(imino)methyl]amino}-2-methoxybenzoate nitrate 
• 1233025-91-6 (5-chloro-2-iodophenyl)(2-fluoro-6-methoxyphenyl)methanone 
• 1028486-08-9 4-{[amino(imino)methyl]amino}-2-methoxybenzoic acid hydrochloride 
• 869367-33-9 8-chloro-4-[(dimethylamino)methylene]-1-(2-fluoro-6-methoxyphenyl)-3,4-dihydro-5H-2-benzazepin-5-one 
• 869366-70-1 tert-butyl {3-[4-chloro-2-(2-fluoro-6-methoxybenzoyl)phenyl]prop-2-yn-1-yl}carbamate 
• 28910-83-0 (2-amino-5-chlorophenyl)-(2,6-difluorophenyl)methanone 
• 869365-97-9 (5-chloro-2-iodophenyl)(2,6-difluorophenyl)methanone 
• 27492-84-8 Methyl 4-amino-2-methoxybenzoate 
• 1028486-10-3 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid ammonium salt 

Downstream Products

• 1028486-06-7 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate sodium salt 

Relevant articles and documents

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