5mg 艾樂替尼/Alectinib （CH5424802）
| 參考價 | ￥ 1421 |
| 訂貨量 | ≥1 |
- 公司名稱 上海高創化學科技有限公司
- 品牌 Selleck
- 型號 5mg
- 產地 美國
- 廠商性質 代理商
- 更新時間 2017/11/20 13:38:13
- 訪問次數 672
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| 供貨周期 | 現貨 | 規格 | 5mg |
|---|---|---|---|
| 貨號 | S2762 | 主要用途 | 科研 |
艾樂替尼/Alectinib (CH5424802)
化學數據
| 分子量 | 482.62 | 穩定性 | 3年 -20°C粉狀 |
|---|---|---|---|
| 化學式 | C30H34N4O2 | -- -- -- | |
| CAS號 | 1256580-46-7 | 別名 | N/A |
| Solubility (25°C) * | 體外 | DMSO | 0.5 mg/mL warmed (1.03 mM) |
| Water | Insoluble | ||
| Ethanol | Insoluble | ||
| 體內 | 30% PEG400+0.5% Tween80+5% propylene glycol | 30 mg/mL | |
| * <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. | |||
| 化學名 | 9-ethyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile | ||
制備儲備液
| 濃度溶劑體積(DMSO)質量 | 1 mg | 5 mg | 10 mg |
| 1 mM | 2.0720 mL | 10.3601 mL | 20.7202 mL |
| 5 mM | - | - | - |
| 10 mM | - | - | - |
| 50 mM | - | - | - |
生物活性
| 產品描述 | Alectinib (CH5424802)是一種有效的ALK抑制劑，在無細胞試驗中IC50為1.9 nM，對L1196M突變型敏感，對ALK比PF-02341066， NVP-TAE684和PHA-E429選擇性高。 | ||||||
|---|---|---|---|---|---|---|---|
| 靶點 |
| ||||||
| 體外研究 | CH5424802作用于ALK 為ATP競爭性的，解離常數(KD)為2.4 nM。CH5424802對ALK 和L1196M 具有強大的抑制效果，Ki分別為0.83 和1.56 nM。 CH5424802 作用于表達EML4-ALK的NCI-H2228 NSCLC細胞，抑制ALK自磷酸化。 CH5424802 也抑制STAT3 和AKT,而不是 ERK1/2的磷酸化。CH5424802 *抑制STAT3在Tyr705位點的磷酸化。CH5424802優先有效作用于表達EML4-ALK的 NCI-H2228細胞，而不作用于融合ALK的陰性 NSCLC細胞系，包括單層培養的HCC827細胞(EGFR外顯子19缺失), A549細胞(KRAS突變), 或NCI-H522細胞(EGFR 野生型, KRAS 野生型, 和ALK野生型)。CH5424802作用于 NCI-H2228球體細胞，引起凋亡標記—caspase-3/7樣激活。CH5424802抑制含NPM-ALK融合蛋白的兩種淋巴瘤細胞, KARPAS-299和SR生長,為不影響不含ALK融合的 HDLM-2淋巴瘤細胞生長。[1] CH5424802 作用于KARPAS-299具有高度靶向選擇性和更強的抗增殖活性。CH5424802抑制KAPRAS-299，IC50為3 nM, 抑制KDR， IC50為1.4 μM。CH5424802代謝穩定性很高。[2] | ||||||
| 體內研究 | CH5424802口服處理，抑制腫瘤生長，這種作用存在劑量依賴性，ED50為0.46 mg/kg。CH5424802按20 mg/kg劑量處理，引起腫瘤快速衰退，衰退達168%,處理11天后(在第28天)每個鼠中的腫瘤體積<30 mm3, 維持有效的抗腫瘤效果，且在4周的無藥處理期間，不會出現腫瘤再生長。CH5424802 處理小鼠的半衰期和口服生物有效性分別為8.6 小時和 70.8%。按6 mg/kg重復劑量處理，在2,7,和24小時后，平均血漿水平達到1.7,1.5,和0.3 nM。CH5424802處理抑制腫瘤生長。CH5424802按20 mg/kg劑量處理 KARPAS-299 和 NB-1，在第20天，腫瘤生長抑制達 119% 和104%。CH5424802 抑制STAT3磷酸化，這種作用存在劑量依賴性(2-20 mg/kg)。CH5424802處理的移植瘤中，觀察到AKT磷酸化部分降低。[1] | ||||||
| 臨床實驗 | |||||||
| 特征 | |||||||
*的實驗操作 (此*來自于公開的文獻所以Selleck并不保證其有效性)
激酶實驗：[1]
| 體外激酶抑制檢測 | 在CH5424802存在時，通過時間分辨熒光共振能量轉移（TR-FRET）分析或熒光偏振（FP）法測量磷酸化各種底物肽的能力，而測評抑制各種激酶（除了MEK1和 Raf-1）的能力。在CH5424802存在時，通過定量分析重組ERK2 蛋白對底物的磷酸化而測評對MEK1的抑制活性。在 CH5424802存在時，通過測定激酶磷酸化MEK1的能力而測評對Raf-1的抑制活性。 |
|---|
細胞實驗：[1]
| 細胞系 | NSCLC, A549 和 HCC827 細胞 |
|---|---|
| 濃度 | 0-1 μM |
| 處理時間 | 5天 |
| 方法 | NSCLC, A549 和HCC827細胞接種在96孔板中過夜，與不同濃度CH5424802按時間溫育。球體細胞生長抑制實驗中，細胞接種在球板上，溫育過夜，然后在時間用化合物處理。通過發光細胞活性檢測存活細胞。使用Caspase-Glo 3/7 檢測試劑盒進行Caspase-3/7檢測。 |
動物實驗：[1]
| 動物模型 | 攜帶NCI-H2228細胞的 SCID 或裸鼠 |
|---|---|
| 配制 | 0.02 N HCl, 10% DMSO, 10% Cremophor EL, 15% PEG400, 和 15% HPCD (2 - 羥丙基-β-環糊精) |
| 劑量 | 20 mg/kg |
| 給藥處理 | 口服處理 |
參考
- [1] Sakamoto H, et al. Cancer Cell. 2011, 19(5), 679-690.
- [2] Kinoshita K, et al. Bioorg Med Chem. 2012, 20(3), 1271-1280.
客戶使用selleck產品的實驗數據
數據來源于[Data independently produced by , , Oncologist, 2017, 22(2):158-164]
Immunoblot analysis of full-length DCTN1-ALK proteins. An expression vector encoding DCTN1-ALK cDNA was introduced into H1299 lung cancer cells, which do not express endogenous ALK. The transfectants were then exposed to crizotinib and alectinib. Levels of phosphorylation at tyrosine 1604 were determined 24 hours after treatment with 0, 0.2, 1.0, or 5.0 μM of each drug.
數據來源于[Data independently produced by Int J Oncol, 2014, 45(4), 1430-6]
Sensitivity of the H3122 cell line to ALK inhibitors (crizotinib and alectinib). To examine the sensitivity of ALK inhibitors, used an MTT assay. The experiment was performed in triplicate. (A) Growth inhibitory effect of crizotinib. The H3122 cell line was sensitive to crizotinib under a normoxic state, compared with a hypoxic state. The graphs, mean of independent triplicate experiments; error bars, SD. (B) IC50 of ALK inhibitors. The IC50 values of both inhibitors in the H3122 cell lines were significantly higher under hypoxia than under normoxia (crizotinib, *P=0.028 and alectinib, *P=0.0035). *P<0.05.
Alectinib (CH5424802)在10個文獻中得到引用
Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms. [Diamond EL,et al. Cancer Discov, 2015, 10.1158/2159-8290.CD-15-0913]
PubMed: 26566875Induction of PD-L1 Expression by the EML4-ALK Oncoprotein and Downstream Signaling Pathways in Non-Small Cell Lung Cancer. [ Clin Cancer Res, 2015, 10.1158/1078-0432.CCR-15-0016]
PubMed: 26019170Receptor ligand-triggered resistance to alectinib and its circumvention by Hsp90 inhibition in EML4-ALK lung cancer cells. [Tanimoto A, et al. Oncotarget, 2014, 5(13):4920-8]
PubMed: 24952482Treatment Efficacy and Resistance Mechanisms Using the Second-Generation ALK Inhibitor AP26113 in Human NPM-ALK–Positive Anaplastic Large Cell Lymphoma [Ceccon M, et al. Mol Cancer Res, 2015, 13(4):775-83]
PubMed: 25421750EMT is associated with, but does not drive resistance to ALK inhibitors among EML4-ALK non-small cell lung cancer [Gower A, et al. Mol Oncol, 2015, 10.1016/j.molonc.2015.11.007]
PubMed: 26639656A guide to picking the most selective kinase inhibitor tool compounds for pharmacological validation of drug targets. [Uitdehaag JC, et al. Br J Pharmacol, 2012, 166(3):858-76]
PubMed: 22250956Hypoxia induces resistance to ALK inhibitors in the H3122 non-small cell lung cancer cell line with an ALK rearrangement via epithelial-mesenchymal transition [Kogita A, et al. Int J Oncol, 2014, 45(4):1430-6]
PubMed: 25096400Activity of second-generation ALK inhibitors against crizotinib-resistant mutants in an NPM-ALK model compared to EML4-ALK. [Fontana D, et al. Cancer Med, 2015, 10.1002/cam4.413]
PubMed: 25727400EMT is associated with, but does not drive resistance to ALK inhibitors among EML4-ALK non-small cell lung cancer. [Gower A, et al. Mol Oncol, 2016, 10(4):601-9]
PubMed: 26639656An Oncogenic ALK Fusion and an RRAS Mutation in KRAS Mutation-Negative Pancreatic Ductal Adenocarcinoma. [Shimada Y, et al. Oncologist, 2017, 22(2):158-164]
PubMed: 28167572
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艾樂替尼/Alectinib (CH5424802)
艾樂替尼/Alectinib (CH5424802)
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