MLN8237 (Alisertib)
(Synonyms: 阿立塞替,MLN 8237) 目录号 : GC12690
Alisertib (MLN8237) 作为一种在研、可口服的选择性极光 A 激酶抑制剂，通常用于治疗实体瘤和血液系统恶性肿瘤。
Cas No.:1028486-01-2
Sample solution is provided at 25 µL, 10mM.
Alisertib (MLN8237), as an investigational, orally available, selective aurora A kinase inhibitor, is usually used for the treatment of solid tumors and hematologic malignancies.[1]
In vitro experiment it shown that treatment with 0.05 μM- 0.5 μM MLN8237 in the leukemia, medulloblastoma, and neuroblastoma cell lines inhibited their cell growth maximumly. However, with >1 μM approximately MLN8237, there was a paradoxical increase in apparent survival in all three lines, most pronounced for Daoy medulloblastoma cell line.[2] In vitro, MLN8237 is effective against both Ewing sarcoma and neuroblastoma cell lines with IC50 of 32 nM and 37 nM, respectively.[4] And alisertib has growth inhibition against U-2 OS cells and MG-63 cells with IC50 of 16.6 μM and 9.5 μM, respectively.[5] In addition, MLN8237 has aggressive inhibition against B-NHL cell proliferation with an IC50 of 10-50 nM and induced apoptosis with a dose- and time-dependent manner.[6]
In vivo, treatment with 30 mg/kg the combination of alisertib and lenvatinib intraperitoneally, every 3 days, for 4 consecutive weeks in BALB/c athymic nude mice, significantly enhanced the antiproliferative and proapoptotic activities, compared with single drugs alone.[3] In vivo efficacy test it indicated that mice were treated with 30 mg/kg MLN8237 for 21 days orally markedly reduced tumor burden and increased overall survival.[7]
References:
[1] Pusalkar S, et al. Biotransformation Pathways and Metabolite Profiles of Oral [14C]Alisertib (MLN8237), an Investigational Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors. Drug Metab Dispos. 2020 Mar;48(3):217-229.
[2] Muscal JA, et al. Additive effects of vorinostat and MLN8237 in pediatric leukemia, medulloblastoma, and neuroblastoma cell lines. Invest New Drugs. 2013 Feb;31(1):39-45.
[3] Hao J, et al. Antitumor Effect of Lenvatinib Combined with Alisertib in Hepatocellular Carcinoma by Targeting the DNA Damage Pathway. Biomed Res Int. 2021 Jul 22;2021:6613439.
[4] Carol H, et al. Efficacy and pharmacokinetic/pharmacodynamic evaluation of the Aurora kinase A inhibitor MLN8237 against preclinical models of pediatric cancer. Cancer Chemother Pharmacol. 2011 Nov;68(5):1291-304.
[5] Niu NK, et al. Pro-apoptotic and pro-autophagic effects of the Aurora kinase A inhibitor alisertib (MLN8237) on human osteosarcoma U-2 OS and MG-63 cells through the activation of mitochondria-mediated pathway and inhibition of p38 MAPK/PI3K/Akt/mTOR signaling pathway. Drug Des Devel Ther. 2015 Mar 12;9:1555-84.
[6] Qi W, et al. Aurora inhibitor MLN8237 in combination with docetaxel enhances apoptosis and anti-tumor activity in mantle cell lymphoma. Biochem Pharmacol. 2011 Apr 1;81(7):881-90.
[7] G?rgün G, et al. A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma. Blood. 2010 Jun 24;115(25):5202-13.
Alisertib (MLN8237) 作为一种在研、可口服的选择性极光 A 激酶抑制剂,通常用于治疗实体瘤和血液系统恶性肿瘤。[1]
体外实验表明,在白血病、髓母细胞瘤和神经母细胞瘤细胞系中用 0.05 μM- 0.5 μM MLN8237 处理可最大程度地抑制它们的细胞生长。然而,在 >1 μM 大约 MLN8237 的情况下,所有三个细胞系的表观存活率都出现了矛盾的增加,对于 Daoy 髓母细胞瘤细胞系最为明显。[2]在体外,MLN8237 对尤文肉瘤和神经母细胞瘤细胞系的 IC50 分别为 32 nM 和 37 nM。[4] alisertib 对 U-2 OS 细胞和 MG-63 细胞具有生长抑制作用,IC50 为 16.6 μM 和 9.5 μM , 分别。[5] 此外,MLN8237 对 B-NHL 细胞增殖具有积极的抑制作用,IC50 为 10-50 nM,并以剂量和时间依赖的方式诱导细胞凋亡。 [6]
在体内,与单独使用单一药物相比,在 BALB/c 无胸腺裸鼠中连续 4 周每 3 天腹膜内注射 30 mg/kg alisertib 和乐伐替尼的组合,显着增强了抗增殖和促凋亡活性。 [3] 体内药效试验表明,小鼠口服 30 mg/kg MLN8237 21 天可显着降低肿瘤负荷并提高总生存期。[7] /p>
| Cell experiment [1]: | |
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Cell lines |
HepG2 and Hep3B cells |
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Preparation Method |
Treated HepG2 and Hep3B cells with various concentrations of alisertib (7-5000 nM) for 48 hours and concentration-survival curves were plotted. |
|
Reaction Conditions |
7-5000 nM; 48 hours |
|
Applications |
The results clearly showed that alisertib inhibited cell growth in a concentration-dependent manner and cotreated with alisertib significantly enhanced the cytotoxicity of lenvatinib. |
| Animal experiment [2]: | |
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Animal models |
MCL SCID mouse xenograft model |
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Dosage form |
10 mg/kg and 30 mg/kg; p.o. |
|
Preparation Method |
There were 6 cohorts of 12 mice: vehicle control, MLN8237 at 10 mg/kg and 30 mg/kg PO once a day for 3 weeks, docetaxol at 10 mg/kg IP once/week × 4, MLN8237 at 10 mg/kg or 30 mg/kg for 3 weeks + docetaxel 10 mg/kg once/week × 4. MLN8237 doses were chosen based on prior dose finding studies provided by Millennium Pharmaceuticals, while docetaxel dose was based on a clinically relevant dose in mouse xenograft tumor model. |
|
Applications |
Both combination treatments with docetaxel significantly increased survival over single agent treatments using MLN8237 (10 mg/kg and 30 mg/kg), and high MLN8237 + docetaxel combination treatment increased survival over single agent treatment with docetaxel. |
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References: Hao J, et al. Antitumor Effect of Lenvatinib Combined with Alisertib in Hepatocellular Carcinoma by Targeting the DNA Damage Pathway. Biomed Res Int. 2021 Jul 22;2021:6613439. |
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| Cas No. | 1028486-01-2 | SDF | |
| 别名 | 阿立塞替,MLN 8237 | ||
| 化学名 | 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid | ||
| Canonical SMILES | COC1=C(C(=CC=C1)F)C2=NCC3=CN=C(N=C3C4=C2C=C(C=C4)Cl)NC5=CC(=C(C=C5)C(=O)O)OC | ||
| 分子式 | C27H20ClFN4O4 | 分子量 | 518.92 |
| 溶解度 | ≥ 25.9 mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9271 mL | 9.6354 mL | 19.2708 mL |
| 5 mM | 0.3854 mL | 1.9271 mL | 3.8542 mL |
| 10 mM | 0.1927 mL | 0.9635 mL | 1.9271 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
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- Purity: >99.00%
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