Selumetinib (AZD6244)
目录号：S1008 别名： ARRY-142886
Molecular Weight(MW): 457.68
Selumetinib (AZD6244)是一种有效，高选择性的MEK抑制剂，对MEK1的IC50为14 nM，对MEK2的Kd值为530 nM。它也抑制ERK1/2磷酸化，IC50为10 nM，对p38α， MKK6， EGFR， ErbB2， ERK2， B-Raf等没有抑制作用。Phase 3。
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客户使用该产品的14个实验数据：
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Left: BRAFV600E A375 cells expressing pLKO or shMED12 vectors were cultured in the absence or presence of 2.5 μM PLX4032 or 0.5 μM AZD6244. The cells were fixed, stained, and photographed after 10 (untreated) or 28 days (treated). Right: A375 cells expressing pLKO or shMED12 vectors were grown in the absence or presence of 1 μM PLX4032 or 0.5 μM AZD6244 for 6 hr.
Cell, 2012, 151(5): 937–950. Selumetinib (AZD6244) purchased from Selleck.
A,ERK phosphorylation in A375 expressing indicated ORFs following treatment with DMSO or 1 μM of PLX4720, RAF265, CI-1040 or AZD6244. B,ERK phosphorylation in A375 expressing indicated ORFs following treatment with DMSO, PLX4720 (1 μM) or PLX4720 in combination with CI-1040 or AZD6244 (all 1 μM).
Nature 2010 468, 968-972. Selumetinib (AZD6244) purchased from Selleck.
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Survival curves for isogenic cell line pairs and melanoma cultures treated with the indicated AZD6244 concentration for 72 h (relative to DMSO treated controls; mean6s.e.m., n55). PLX4032 resistant cells were grown with PLX4032. Dashed line, 50% cell killing.
Nature 2010 468, 973-977. Selumetinib (AZD6244) purchased from Selleck.
a-c, Inhibitors of BRAFV600E (PLX4032) and MEK1/2 (PD98059 or AZD6244) increase PGC1α and ID2 expression (a, b) and repress integrin expression and signalling (b, c). Cells were treated with indicated concentration of inhibitors for 6 h (a, b) or 24 h (c). d, e, PLX4032 increases the interaction between ID2 and TCF4 (d) and decreases the occupancy of TCF4 at the promoters of integrin genes (e). f–g, PGC1α and ID2 are partially required for PLX4032-mediated inhibition of invasion and metastasis. For in vitro assays (f), A375 cells were incubated with 1 μM PLX4032 for 10 h. Images represent one picture captured per membrane with the scale bar representing 200 μm. Values in a, b, e and f represent mean±s.d. of independent biological triplicates; *P<0.05 and **P<0.01 by Student's t-test in a, b, e, f.
Nature, 2016, 537(7620):422-428.. Selumetinib (AZD6244) purchased from Selleck.
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Parental murine KRasG12V;p53-/- lung cancer cells or the same cell lines stably expressing exogenous KRASWT or KRASD154Q were injected intravenously into nude mice. After one week, animals were treated with selumetinib (50 mg/kg daily) and sacrificed at the indicated time points. Lungs were lysed and analyzed by western blot with the indicated antibodies.
Cell, 2018, 172(4):857-868. Selumetinib (AZD6244) purchased from Selleck.
A and B, clonogenic assays in 2 melanoma cell lines (YUVON and YUSIK) treated with NVPBEZ235 (BEZ) and AZD6244 (AZD) alone and in combination. Combinations were more effective in inhibiting colony formation at lower concentrations than either drug alone.
Clin Cancer Res 2010 16, 6029-6039. Selumetinib (AZD6244) purchased from Selleck.
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Ex vivo and functional characterization of MEK1(P124L). (A) AZD6244-mediated growth inhibition ex vivo of treatment-naïve BRAFV600E melanoma cells (black and blue) or cells cultured from an AZD6244-resistant metastatic focus (red). (B) ERK phosphorylation (p-ERK) andMEKphosphorylation (p-MEK) are shown following treatment with increasing concentrations of AZD6244 in treatment-naïve or AZD6244-resistant melanoma cells cultured ex vivo. The tubulin loading control (-tubulin) is also shown. (C) AZD6244 growth inhibition curves of parental A375 (solid black), A375 cells expressing MEK-DD (grey), wild-type MEK1 (hatched black), or MEK1(P124L) (red) are shown. In each instance n6 anderrorstandard deviation. (D) p-ERK and p-MEK are shown following treatment with increasing AZD6244 concentrations in the cell lines described in C, Above. The -tubulin control is also shown.
Proc Natl Acad Sci USA 2009 106, 20411-20416. Selumetinib (AZD6244) purchased from Selleck.
AZD6244 enhanced FOXO3a expression and induced suppression of cancer cell proliferation. A, tumor volume of the HCT116 xenografts treated with Placebo or AZD6244 was measured for 21 d. The tumor sections of four individual DMSO or AZD6244-treated HCT116 xenografts were subjected to immunohistochemistry with a FOXO3a antibody. Relative percentages of nuclear FOXO3a expression of individual xenograft tumors from B were analyzed and the mean values of FOXO3a expression in Placebo or AZD6244-treated group were indicated as bars.
Cancer Res 2010 70, 4709-4718. Selumetinib (AZD6244) purchased from Selleck.
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lysates from various cancer cell lines: breast cancer (MDA-MB-435), colon cancer (HCT116, SW620, and HT29), and melanoma (WM793) treated with DMSO or AZD6244 (10 μmol/L) for 4 h were subjected to immunoblotting with the indicated antibodies.
Cancer Res 2010 70, 4709-4718. Selumetinib (AZD6244) purchased from Selleck.
Stimulation response of p37d-expressing cells. (c) Western blot of 5 min serum stimulated HEK-293 cells stably expressing p37d, p110d or control, with the presence of inhibitors as indicated at the top.
Oncogene 2012 31, 3277–3286. Selumetinib (AZD6244) purchased from Selleck.
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Concentration equilibrium transport assays (CETAs) for selumetinib using parental and (murine) Mdr1a or (human) MDR1 overexpressing LLC cells. Zosuquidar (5 μM) was used to specifically inhibit P-gp mediated transport. Data are means ± SD; n = 6; ** p < 0.01, *** p < 0.001.
Int J Cancer, 2018, 142(2):381-391. Selumetinib (AZD6244) purchased from Selleck.
INA-6 MM cells were treated with AS703026 or AZD6244 for 2 d, followed by [3H]thymidine uptake assay. PBMCs isolated from normal donors (n = 3) were incubated with M-CSF and RANKL, in the presence or absence of AS703026 or AZD6244 for 14 d. The TRAP assay was performed to measure the formation of multinuclear osteoclast cells (OC).
Br J Haematol 2010 149, 537–549. Selumetinib (AZD6244) purchased from Selleck.
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B-RafV600E mutated melanoma line,A375, was treated with different doses of AZD6244 for 1hour or 24 hours.Cell lysates were analyzed by Western Blotting to determine the levels of phosphorylated ERK1/2(Perk1/2)
Dr. Jong-In Park of Medical College of Wisconsin. Selumetinib (AZD6244) purchased from Selleck.
Selumetinib (AZD6244) purchased from Selleck.
产品安全说明书
MEK抑制剂选择性比较
生物活性
| 产品描述 | Selumetinib (AZD6244)是一种有效，高选择性的MEK抑制剂，对MEK1的IC50为14 nM，对MEK2的Kd值为530 nM。它也抑制ERK1/2磷酸化，IC50为10 nM，对p38α， MKK6， EGFR， ErbB2， ERK2， B-Raf等没有抑制作用。Phase 3。 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 特性 | AZD6244是第一个处于随机二期研究的MEK抑制剂。 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 靶点 |
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| 体外研究 |
AZD6244是ATP非竞争性的抑制剂，在IC50浓度小于40 nM时使ERK1/2的磷酸化作用失活。AZD6244也通过抑制ERK1/2和p90RSK的磷酸化抑制原代HCC细胞的生长，同时伴随着caspase-3和caspase-7分裂的加强, 及断裂的聚腺苷二磷酸核糖聚合酶的增多。AZD6244在P38，JNK，PI3K，及MEK5/ERK5通路中的作用不大。[1]AZD6244对感知乳腺癌细胞系中的raf突变和非小细胞肺癌细胞系中的ras突变很灵敏。[2] |
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| Cell Data |
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| 体内研究 | 活体研究显示AZD6244在2-1318, 5-1318, 及26-1004 4-1318移植物中明显抑制ERK1/2的磷酸化，并且在原代2-1318细胞中通过激活caspase通路诱导细胞凋亡。[1]HT-29移植瘤是携带B-raf突变的直肠瘤模型，AZD6244 在100mg/kg剂量时可以抑制HT-29移植瘤中肿瘤的增长，并且AZD6244作用下的肿瘤指数比吉西他滨作用下的肿瘤指数要好[3]。另外，AZD6244可以抑制HCC移植瘤的增长，HCC移植瘤的增长与细胞凋亡的增多，及细胞周期调控的减量调节有关。包括：cyclin D1, cdc-2, CDK 2 ,CDK4, cyclin B1, 及 c-Myc。[4] |
推荐的实验操作(此推荐来自于公开的文献所以Selleck并不保证其有效性)
| 激酶实验： |
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激酶实验: 在杆状病毒感染的hi5昆虫细胞中表达的组成型的氮端用六聚组氨酸标记的MEK1，通过金属亲和层析、离子交换及凝胶过滤纯化。MEK1的活性评估通过测量[γ-33P]ATP 作用于ERK2的示踪[γ-33P]磷酸的渗透率。实验在96孔板中进行，保温混合物由25 mM HEPES (pH 7.4), 10 mM MgCl2, 5 mM β-甘油磷酸 100 μM 原钒酸钠, 5 mM DTT, 5 nM MEK1, 1 μM ERK2, 和AZD6244 (溶解在 1% DMSO)组成。加入10 μM ATP (0.5 μC k[γ-33P]ATP/每孔)反应开始，然后在室温下温育45分钟。加入同等量的25%的三氯乙酸反应停止，使蛋白沉淀。沉淀的蛋白加到玻璃纤维过滤板上，用0.5%的磷酸冲洗掉过量的示踪ATP，然后在液体闪烁计数管中计算放射性。通过在反应混合物中改变ATP的量来决定ATP相关性。 |
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| 细胞实验： |
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| 动物实验： |
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参考文献
- [1] Huynh H, et al, Mol Cancer Therapy, 2007, 6 (1), 138-146
- [2] Garon EB, et al, Mol Cancer Thera, 2010, 9 (7), 1985-1994.
- [3] Yeh TC, et al, Clin Cancer Res, 2007, 13 (5), 1576-1583.
- [4] Huynh H, et al, Mol Cancer Ther, 2007, 6 (9), 2468-2476.
- [5] Davies BR, et al. Mol Cancer Ther, 2007, 6(8), 2209-2219.
- [6] Morelli MP, et al. Clin Cancer Res, 2012, 18(4), 1051-1062.
- [7] Yuen JS, et al. Int J Oncol, 2012, 41(2), 712-720.
- [8] Leboeuf R, et al. J Clin Endocrinol Metab, 2008, 93(6), 2194-2201.
- [9] Emery CM,, et al. Proc Natl Acad Sci U S A, 2009, 106(48), 20411-20416.
- [10] Friday BB, et al. Cancer Res, 2008, 68(15), 6145-6153.
- [11] Huynh H, et al. J Hepatol, 2010, 52(1), 79-87.
- [12] Diep CH, et al. Clin Cancer Res, 2011, 17(9), 2744-2756.
- [13] Davis MI, et al. Nat Biotechnol. 2011, 29(11):1046-51.
溶解度 (25°C)
| 体外 | DMSO | 91 mg/mL warmed (198.82 mM) |
|---|---|---|
| Water | Insoluble | |
| Ethanol | Insoluble | |
| 体内 |
从左到右依次将纯溶剂加入产品，现配现用(数据来自Selleck实验检测而非文献)： 4% DMSO+30% PEG 300+5% Tween 80+ddH2O |
5mg/mL |
* 溶解度检测是由Selleck技术部门检测的，可能会和文献中提供的溶解度有所差异，这是由于生产工艺和批次不同产生的正常现象。请按照顺序依次加入各个纯溶剂。
化学数据
| 分子量 | 457.68 |
|---|---|
| 化学式 | C17H15BrClFN4O3 |
| CAS号 | 606143-52-6 |
| 稳定性 | powder |
| in solvent | |
| 别名 | ARRY-142886 |
计算器
摩尔浓度计算器
本计算器可帮助您计算出特定溶液中溶质的质量、溶液浓度和体积之间的关系，公式为:
质量 (g) = 浓度 (mol/L) x 体积 (L) x 分子量 (g/mol)
摩尔浓度计算公式
*在配置溶液时，请务必参考Selleck产品标签上、MSDS / COA（可在Selleck的产品页面获得）批次特异的分子量使用本工具。
稀释计算器
用本工具协助配置特定浓度的溶液，使用的计算公式为：
开始浓度 x 开始体积 = 最终浓度 x 最终体积
稀释公式
稀释公式一般简略地表示为: C1V1 = C2V2 ( 输入 输出 )
在配置溶液时，请务必参考Selleck产品标签上、MSDS / COA（可在Selleck的产品页面获得）批次特异的分子量使用本工具。.
分子量计算器
通过输入化合物的化学式来计算其分子量：
注：化学分子式大小写敏感。C10H16N2O2 c10h16n2o2
摩尔浓度计算器
临床试验信息
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT03433183 | Not yet recruiting | Malignant Peripheral Nerve Sheath Tumors|Neurofibromatosis 1 | Sarcoma Alliance for Research through Collaboration|United States Department of Defense|AstraZeneca | December 2018 | Phase 2 |
| NCT03326388 | Not yet recruiting | Neurofibromatosis Type 1|Plexiform Neurofibroma|Optic Nerve Glioma | Great Ormond Street Hospital for Children NHS Foundation Trust|AstraZeneca | December 2018 | Phase 1|Phase 2 |
| NCT03581487 | Not yet recruiting | Recurrent Non-Small Cell Lung Carcinoma|Stage IV Lung Cancer|Stage IVA Lung Cancer|Stage IVB Lung Cancer | M.D. Anderson Cancer Center|National Cancer Institute (NCI) | November 2018 | Phase 1|Phase 2 |
| NCT03109301 | Recruiting | Neoplasms Nerve Tissue|Neurofibromatosis 1|Heredodegenerative Disorders Nervous System|Peripheral Nervous System Diseases | National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC) | November 20 2018 | Phase 2 |
| NCT03742102 | Not yet recruiting | Triple Negative Breast Neoplasms | AstraZeneca | November 30 2018 | Phase 1|Phase 2 |
| NCT03326310 | Recruiting | Chronic Myeloid Leukemia|Myelofibroses | University of Chicago | September 4 2018 | Phase 1 |
技术支持
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如果有其他问题，请给我们留言。
常见问题及建议解决方法
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问题 1：
How about the solubility of S1008? How to prepare for the solution if I need to do the in vivo experiments?
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回答：
S1008 AZD6244 in vehicle 5% DMSO+30% PEG 300+ddH2O will be a suspension for oral administration. If you want a clear solution for injection, you can dissolve it in 4% DMSO+30% PEG 300+5% Tween 80+ddH2O.
