5mg 艾乐替尼/Alectinib （CH5424802）

艾乐替尼/Alectinib (CH5424802)

化学数据

分子量	482.62	稳定性	3年 -20°C粉状
化学式	C30H34N4O2		-- -- --
CAS号	1256580-46-7	别名	N/A
Solubility (25°C) *	体外	DMSO	0.5 mg/mL warmed (1.03 mM)
		Water	Insoluble
		Ethanol	Insoluble
	体内	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.
化学名	9-ethyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

制备储备液

浓度溶剂体积(DMSO)质量	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

产品描述	Alectinib (CH5424802)是一种有效的ALKYZ剂，在无细胞试验中IC50为1.9 nM，对L1196M突变型敏感，对ALK比PF-02341066， NVP-TAE684和PHA-E429选择性高。
靶点	ALK (F1174L) [1] (Cell-free assay) ALK [1] (Cell-free assay) ALK (R1275Q) [1] (Cell-free assay) 1 nM 1.9 nM 3.5 nM
体外研究	CH5424802作用于ALK 为ATP竞争性的，解离常数(KD)为2.4 nM。CH5424802对ALK 和L1196M 具有强大的YZ效果，Ki分别为0.83 和1.56 nM。 CH5424802 作用于表达EML4-ALK的NCI-H2228 NSCLC细胞，YZALK自磷酸化。 CH5424802 也YZSTAT3 和AKT,而不是 ERK1/2的磷酸化。CH5424802 完全YZSTAT3在Tyr705位点的磷酸化。CH5424802优先有效作用于表达EML4-ALK的 NCI-H2228细胞，而不作用于融合ALK的阴性 NSCLC细胞系，包括单层培养的HCC827细胞(EGFR外显子19缺失), A549细胞(KRAS突变), 或NCI-H522细胞(EGFR 野生型, KRAS 野生型, 和ALK野生型)。CH5424802作用于 NCI-H2228球体细胞，引起凋亡标记—caspase-3/7样激活。CH5424802YZ含NPM-ALK融合蛋白的两种淋巴瘤细胞, KARPAS-299和SR生长,为不影响不含ALK融合的 HDLM-2淋巴瘤细胞生长。[1] CH5424802 作用于KARPAS-299具有高度靶向选择性和更强的抗增殖活性。CH5424802YZKAPRAS-299，IC50为3 nM, YZKDR， IC50为1.4 μM。CH5424802代谢稳定性很高。[2]
体内研究	CH5424802口服处理，YZ肿瘤生长，这种作用存在剂量依赖性，为0.46 mg/kg。CH5424802按20 mg/kg剂量处理，引起肿瘤快速衰退，衰退达168%,处理11天后(在第28天)每个鼠中的肿瘤体积<30 mm3, 维持有效的抗肿瘤效果，且在4周的无药处理期间，不会出现肿瘤再生长。CH5424802 处理小鼠的半衰期和口服生物有效性分别为8.6 小时和 70.8%。按6 mg/kg重复剂量处理，在2,7,和24小时后，平均血浆水平达到1.7,1.5,和0.3 nM。CH5424802处理YZ肿瘤生长。CH5424802按20 mg/kg剂量处理 KARPAS-299 和 NB-1，在第20天，肿瘤生长YZ达 119% 和104%。CH5424802 YZSTAT3磷酸化，这种作用存在剂量依赖性(2-20 mg/kg)。CH5424802处理的移植瘤中，观察到AKT磷酸化部分降低。[1]
临床实验
特征

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：[1]

体外激酶YZ检测	在CH5424802存在时，通过时间分辨荧光共振能量转移（TR-FRET）分析或荧光偏振（FP）法测量磷酸化各种底物肽的能力，而测评YZ各种激酶（除了MEK1和 Raf-1）的能力。在CH5424802存在时，通过定量分析重组ERK2 蛋白对底物的磷酸化而测评对MEK1的YZ活性。在 CH5424802存在时，通过测定激酶磷酸化MEK1的能力而测评对Raf-1的YZ活性。

细胞实验：[1]

细胞系	NSCLC, A549 和 HCC827 细胞
浓度	0-1 μM
处理时间	5天
方法	NSCLC, A549 和HCC827细胞接种在96孔板中过夜，与不同浓度CH5424802按指定时间温育。球体细胞生长YZ实验中，细胞接种在球板上，温育过夜，然后在指定时间用化合物处理。通过发光细胞活性检测存活细胞。使用Caspase-Glo 3/7 检测试剂盒进行Caspase-3/7检测。

动物实验：[1]

动物模型	携带NCI-H2228细胞的 SCID 或裸鼠
配制	0.02 N HCl, 10% DMSO, 10% Cremophor EL, 15% PEG400, 和 15% HPCD (2 - 羟丙基-β-环糊精)
剂量	20 mg/kg
给药处理	口服处理

 

参考

• [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.

客户使用selleck产品的实验数据

数据来源于[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.

数据来源于[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个文献中得到引用

• Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms. [Diamond EL,et al. Cancer Discov, 2015, 10.1158/2159-8290.CD-15-0913]

  PubMed: 26566875

• Induction 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: 26019170

• Receptor 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: 24952482

• Treatment 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: 25421750

• EMT 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: 26639656

• A 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: 22250956

• Hypoxia 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: 25096400

• Activity 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: 25727400

• EMT 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: 26639656

• An 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

如果需要长期保存，请于零下二十度低温保存。

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艾乐替尼/Alectinib (CH5424802)

艾乐替尼/Alectinib (CH5424802)