BI-847325
目录号 : GC17828
A selective dual MEK/Aurora kinase inhibitor
Cas No.:1207293-36-4
Sample solution is provided at 25 µL, 10mM.
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BI 847325 is a dual inhibitor of Ras-mitogen-activated protein kinase kinases (MEK) and Aurora kinases [1,2]. BI 847325 inhibits MEK1 and MEK2 with IC50 values of 25 and 4 nM, respectively. For inhibiting the activity of Aurora A, B and C, IC50 values are 3, 25 and 15 nM, respectively [1].
The RAS-dependent MAP kinase signaling pathway is important in the regulation of cell survival and proliferation. It is hard to design direct inhibitors of RAS proteins. MEK is a downstream kinase of MAP kinase [1]. MEK is a ERK kinase [3].
In cells treated with BI 847325, based on levels of phospho-histone H3 (pHH3) and phospho-ERK (pERK), EC50 values were determined. To KRAS-and-PI3Kα-mutant NCI-H460 cells, the EC50 value was 44 nM. To BRAF-mutant A375 cells, the EC50 value was 37 nM. In a panel of 240 cell lines from diverse tissues with diverse genetic background, BI 847325 produced a potent inhibition of cell proliferation with a gm GI50 value of 28 nM. In a subset of cell lines, BI 847325 induced cell death. These in vitro potency correlated with mutations in BRAF or RAS, significantly [1].
In nude mouse xenograft models of cutaneous melanoma (A375, mutant BRAF) and NSCLC (Calu-6, mutant KRAS), BI 847325 at a daily oral dose of 10 mg/kg produced complete inhibition of tumor growth. In animals with A375 tumors, treatment with BI 847325 significantly reduced levels of both pHH3 and pERK in the tumors compared to controls [1].
References:
[1]. Sini P, Gürtler U, Zahn SK, et al. Pharmacological characterization of BI 847325, a dual inhibitor of MEK and Aurora kinases. Cancer Research, 2012, 72(8 Supplement): 1919-1919.
[2]. Hideshima T, Chauhan D, Richardson P, et al. NF-κB as a therapeutic target in multiple myeloma. Journal of Biological Chemistry, 2002, 277(19): 16639-16647.
[3]. Rommel C, Clarke BA, Zimmermann S, et al. Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt. Science, 1999, 286(5445): 1738-1741..
Kinase experiment: | Assays are run in the presence of 100 μM ATP using 10 μM of substrate. 30 μL PROTEIN-MIX in 25% DMSO and incubated for 15 min at room temperature. 10 μL PEPTIDE-MIX is added, the mixture is incubated for 60 min at RT and stopped by adding 180 μL 6.4% TCA (final concentration: 5%). Incorporated phosphate is measured in a scintillation counter and IC50 values are calculated using a sigmoidal curve analysis program with variable hill slope[1]. |
Cell experiment: | Cells are plated in 96-well format and BI 847325 is added 24 hours after cell seeding. At the same time, a “time zero” untreated cell plate is fixed. Compound is serially diluted and assayed over 8 concentrations in triplicates. After 72 h incubation, cells are fixed and stained with fluorescent nuclear dye. Concentration–response curves are analyzed using a four-parameter log-logistic function without upper or lower limitation. GI50 are calculated[1]. |
Animal experiment: | Mice: Tumor grafted female BomTac:NMRI-Foxn1nu mice are used in the study. BI 847325 is dissolved in 0.5% Natrosol 250 HX with 3% Tween 80 and sonicated until a homogenous suspension is obtained, then 1 M HCl is added and the suspension is vortexed and sonicated again. MEK inhibitors GSK 1120212 and AZD 6244 are suspended in 1% or 0.5% Natrosol, respectively. An administration volume of 10 mL/kg body weight is used and compounds are administered orally with a gavage needle at the indicated dose and schedule. Tumor volumes are measured and mice are inspected daily for clinical signs and body weight is determined daily[1]. |
References: [1]. Sini P, et al. Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-Competitive Inhibitor of MEK and Aurora Kinases. Mol Cancer Ther. 2016 Oct;15(10):2388-2398. | |
| Cas No. | 1207293-36-4 | SDF | |
| 化学名 | (Z)-3-(3-(((4-((dimethylamino)methyl)phenyl)amino)(phenyl)methylene)-2-oxoindolin-6-yl)-N-ethylpropiolamide | ||
| Canonical SMILES | CCNC(C#CC1=CC=C2C(NC(/C2=C(NC3=CC=C(CN(C)C)C=C3)/C4=CC=CC=C4)=O)=C1)=O | ||
| 分子式 | C29H28N4O2 | 分子量 | 464.56 |
| 溶解度 | DMF: 16 mg/ml,DMF:PBS(pH 7.2)(1:6): 0.14 mg/ml,DMSO: 5 mg/ml,Ethanol: 0.3 mg/ml | 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 | 2.1526 mL | 10.7629 mL | 21.5257 mL |
| 5 mM | 0.4305 mL | 2.1526 mL | 4.3051 mL |
| 10 mM | 0.2153 mL | 1.0763 mL | 2.1526 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。
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Quality Control & SDS
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- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet