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Neratinib (HKI-272)

现货
Catalog No.
A8322
HER2/EGFR抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 900.00
现货
5mg
¥ 500.00
现货
25mg
¥ 1,200.00
现货

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Background

IC50: 59 nM (Her-2); 92 nM (EGFR)
HER-2 belongs to the ErbB family of receptor tyrosine kinases, which has been implicated in a variety of cancers. Overexpression of HER-2 is seen in 25–30% of breast cancer patients and predicts a poor outcome in patients with primary disease. Neratinib (HKI-272) is a tyrosine kinase inhibitor under investigation for the treatment breast cancer and other solid tumours.
In vitro: Neratinib (HKI-272) is a potent inhibitor of HER-2 and is highly active against HER-2-overexpressing human breast cancer cell lines in vitro. It also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells. Neratinib reduces HER-2 receptor autophosphorylation in cells at doses consistent with inhibition of cell proliferation and functions as an irreversible binding inhibitor, most likely by targeting a cysteine residue in the ATP-binding pocket of the receptor. In agreement with the predicted effects of HER-2 inactivation, Neratinib treatment of cells results in inhibition of downstream signal transduction events and cell cycle regulatory pathways. This leads to arrest at the G1-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle, ultimately resulting in decreased cell proliferation [1].
In vivo: In vivo, Neratinib is active in HER-2- and EGFR-dependent tumor xenograft models when dosed orally on a once daily schedule. On the basis of its favorable preclinical pharmacological profile, Neratinib has been selected as a candidate for additional development as an antitumor agent in breast and other HER-2-dependent cancers [1].
Clinical trial: Neratinib is in development for the treatment of early- and late-stage HER2-positive breast cancer. Neratanib is being developed by Puma Biotechnology. It will be included in the forthcoming I-SPY2 breast cancer trial (http://en.wikipedia.org/wiki/Neratinib).
Reference:
[1] Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, Hallett WA, Johnson BD, Nilakantan R, Overbeek E, Reich MF, Shen R, Shi X, Tsou HR, Wang YF, Wissner A. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 2004;64(11):3958-65.

文献引用

1. Duggan BM, Foley KP, et al. "Tyrosine kinase inhibitors of Ripk2 attenuate bacterial cell wall-mediated lipolysis, inflammation and dysglycemia." Sci Rep. 2017 May 8;7(1):1578. PMID:28484277

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt557.04
Cas No.698387-09-6
FormulaC30H29ClN6O3
SynonymsHKI-272;HKI272;HKI 272
Solubility≥13.9mg/mL in DMSO with gentle warming
Chemical Name(E)-N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide
SDFDownload SDF
Canonical SMILESCCOC1=C(C=C2C(=C1)N=CC(=C2NC3=CC(=C(C=C3)OCC4=CC=CC=N4)Cl)C#N)NC(=O)C=CCN(C)C
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验 [1]:

自磷酸化试验

使用DMSO配制10 mg/mL的Neratinib储备液,再用25 mM HEPES (pH 7.5; 0.002 ng/mL ~ 20 μg/mL) 进行稀释。在96孔ELISA板上,将纯化的重组HER-2羧基末端片段(第676 ~ 1255位氨基酸)或EGFR羧基末端片段(第645 ~ 1186位氨基酸)[用100 mM HEPES (pH 7.5) 和50%甘油进行稀释]和浓度不断增高的Neratinib加入4 mM HEPES (pH 7.5),0.4 mM MnCl2,20 μM钒酸钠以及0.2 mM DTT中,化合物于室温下孵育15分钟。加入40 μM ATP和20 mM MgCl2开始激酶反应,然后将其置于室温下反应1小时。冲洗实验板,使用铕标记的抗磷酸化酪氨酸抗体 (15 ng/well) 测定磷酸化。冲洗后,使用Victor2荧光读数仪(激发波长为340 nm,发射波长为615 nm)检测信号。通过抑制曲线计算IC50值。

细胞实验 [1]:

细胞系

3T3、3T3/neu、A431、BT474、SK-Br-3、MDA-MB-435和SW480细胞

制备方法

在DMSO中的溶解度有限。若配制更高浓度的溶液,一般步骤如下:请将试管置于37 °C加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20 °C可放置数月。

反应条件

0.5 ng/mL ~ 5 μg/mL;2或6天

实验结果

Neratinib选择性地抑制过表达HER2的3T3/neu、SK-Br-3和BT474细胞增殖,其IC50值为2 ~ 3 nM。Neratinib对过表达HER2的细胞的作用比对未转染的3T3细胞以及EGFR和HER2阴性的MDA-MB-435和SW620细胞的作用强230多倍。此外,Neratinib也抑制EGFR阳性A431细胞的增殖,其IC50值为81 nM。

动物实验 [1]:

动物模型

携带3T3/neu和BT474细胞的裸小鼠

给药剂量

5、10、20、40和80 mg/kg/day;口服给药

实验结果

在携带3T3/neu细胞的裸小鼠中,Neratinib显著抑制肿瘤生长(10、20、40和80 mg/kg/day剂量对应的肿瘤生长抑制率分别为34%、53%、98%和98%)。在剂量为5、10和40 mg/kg/day,Neratinib对BT474异种移植瘤的生长抑制率分别为70 ~ 82%、67%和93%。

注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1]. Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, Hallett WA, Johnson BD, Nilakantan R, Overbeek E, Reich MF, Shen R, Shi X, Tsou HR, Wang YF, Wissner A. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 2004;64(11):3958-65.

生物活性

描述 Neratinib(HKI-272)是一种高选择性的HER2和EGFR抑制剂,IC50值分别为59 nM和92 nM。
靶点 HER2 EGFR        
IC50 59 nM 92 nM        

质量控制

化学结构

Neratinib (HKI-272)

相关生物数据

Neratinib (HKI-272)