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SNS-314 Mesylate

产品号 S1154 公司名称 Selleck Chemicals
CAS号 1146618-41-8 公司网站 http://www.selleckchem.com
分子式 C19H19ClN6O4S3 电 话 (877) 796-6397
分子量 527.03996 传 真 (832) 582-8590
纯 度 电子邮件 sales@selleckchem.com
保 存 -20°C Chembase数据库ID: 72548

产品价格信息

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产品别名

标题
SNS-314 Mesylate
IUPAC标准名
1-(3-chlorophenyl)-3-{5-[2-({thieno[3,2-d]pyrimidin-4-yl}amino)ethyl]-1,3-thiazol-2-yl}urea; methanesulfonic acid
IUPAC传统名
1-(3-chlorophenyl)-3-[5-(2-{thieno[3,2-d]pyrimidin-4-ylamino}ethyl)-1,3-thiazol-2-yl]urea mesylate

产品登记号

CAS号 1146618-41-8

产品性质

作用靶点 Aurora Kinase
成盐信息 Mesylate
溶解度 DMSO
保存条件 -20°C

产品详细信息

详细说明 (English)
Research Area
Description Cancer
Biological Activity
Description SNS-314 Mesylate is a potent and selective inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 9 nM, 31 nM, and 3.4 nM, respectively.
Targets Aurora A Aurora B Aurora C
IC50 9 nM 31 nM 3.4 nM [1]
In Vitro In HCT116 colorectal carcinoma cell line, with intact or depleted p53 protein levels, SNS-314 Mesylate shows enhanced efficacy when administered sequentially with other standard chemotherapeutic agents and the most profound synergies are identified for agents that activate the spindle assembly checkpoint, e.g., docetaxel and vincristine. [2] A recent study shows that SNS-314 Mesylate shows potent antiproliferative activity in HCT116 cells and inhibits soft agar colony formation. [3]
In Vivo The sequential treatment with SNS-314 Mesylate followed by docetaxel 24 hours later produces a significant 72.5% tumor growth inhibition of HCT116 xenografts, while docetaxel and SNS-314 Mesylate as single agents produce no significant inhibition of HCT116 tumor growth. [2] In the HCT116 human colon cancer xenograft model, administration of 50 and 100 mg/kg SNS-314 Mesylate results a dose-dependent inhibition of histone H3 phosphorylation, indicating effective Aurora-B inhibition in vivo. In addition, HCT116 tumors from animals treated with SNS-314 Mesylate exhibits potent and sustained responses including reduction of phosphorylated histone H3 levels, increased caspase-3 and appearance of increased nuclear size. [3]
Clinical Trials SNS-314 Mesylate is currently in Phase I clinical trials in patients with advanced solid tumors
Features
Protocol
Kinase Assay [1]
Aurora-A Kinase Assay Humanized mouse Aurora A (amino acids 107-403) is expressed in E. coli as described previously. For IC50 assays, compounds are titrated three-fold in DMSO and diluted 12.5-fold into assay buffer (10 mM Tris HCl pH 7.2, 10 mM MgCl2, 0.05% NaN3, 0.01% Tween-20, and 0.1% BSA). Compounds are then diluted 4-fold into assay buffer containing Aurora A and FAM-PKAtide at final concentrations of 2 nM and 50 nM, respectively. The kinase reaction is initiated by adding ATP in assay buffer at a final concentration of 10 mM and incubated at 21 °C for 25 minutes. As a positive control, DMSO is added instead of compound and as a negative control assay buffer is added instead of Aurora A. Both control reactions are conducted in triplicate. To detect phosphorylated PKAtide, the kinase reaction is combined with Progressive Binding Solution (1:400 Progressive Binding Reagent, 1× Buffer A, Molecular Devices) in a 1:3 ratio. The mixture is incubated for 30 minutes at 21 °C and the plate is scanned on an Analyst AD with excitation at 485 nm and emission at 530 nm. The percent relative enzymatic activity is calculated by normalizing the mP value for each well to the average positive control. Relative enzymatic activity values are plotted as a function of the logarithm of compound concentration and IC50 values are generated in GraphPad Prism software using a sigmoidal dose-response curve-fit. IC50’s are calculated as the concentration of compound at which enzymatic activity is 50%.
Cell Assay [2]
Cell Lines HCT116 SCR and HCT116 p53 RNAi cells
Concentrations ~125 nM
Incubation Time 48 hours
Methods Viability is measured using the CellTiter-Blue cell viability assay. Cells are treated as described above, although with a 5-day incubation period. Cytotoxicity is determined by measuring intracellular ATP using the CellTiter-Glo Luminescence Cell Viability Assay. Cells are seeded in white 96-well tissue culture plates at a density of 1.5-2 × 103 cells/well, and a serial dilution of SNS-314 is dosed in combination with fixed concentrations of either docetaxel or vincristine for a total of 72 hours. Viability is determined as the ratio between the ATP in treated cells versus control cells. Apoptosis is measured using the caspase-Glo 3/7 system. Cells are plated in white 96-well plates as described above and treated first with SNS-314 for 24 hours, washed with 200 μL of 1× PBS, and fresh medium is added with the second agent for 24 hours.
Animal Study [2]
Animal Models HCT116 cells are injected s.c. into the right flank of nu/nu mice.
Formulation SNS-314 is formulated in 20% Captisol R.
Doses ≤42.5 mg/kg
Administration Administered via i.p.
References
[1] Oslob JD, et al. Bioorg Med Chem Lett, 2008, 18(17), 4880-4884.
[2] VanderPorten EC, et al. Mol Cancer Ther, 2009, 8(4), 930-939.
[3] Arbitrario JP, et al. Cancer Chemother Pharmacol, 2010, 65(4), 707-717.