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Neratinib

Neratinib

产品编号 T2325   CAS 698387-09-6
别名: HKI-272, 来那替尼

Neratinib (HKI-272) 是一种口服的、不可逆的酪氨酸激酶抑制剂,对 HER2 和 EGFR 的 IC50值分别为 59 和 92 nM。

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Neratinib Chemical Structure
Neratinib, CAS 698387-09-6
规格 价格/CNY 货期 数量
5 mg ¥ 282 现货
10 mg ¥ 497 现货
25 mg ¥ 788 现货
50 mg ¥ 1,080 现货
100 mg ¥ 1,890 现货
200 mg ¥ 3,490 现货
500 mg ¥ 5,580 现货
其他形式的 Neratinib:
产品目录号及名称: Neratinib (T2325)
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纯度: 100%
纯度: 98.55%
纯度: 98.16%
纯度: 96.17%
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生物活性
化学信息
存储 & 溶解度
参考文献
产品描述 Neratinib (HKI-272) (HKI-272) is an orally available, irreversible tyrosine kinase inhibitor for HER2 and EGFR (IC50: 59/92 nM), respectively.
靶点活性 EGFR:92 nM (cell free), HER2:59 nM (cell free)
体外活性 In a cell-free autophosphorylation assay using the recombinant cytoplasmic domain of HER-2, Neratinib (HKI-272) reduced kinase activity by 50% (IC50) at a concentration of 59 nM. It weakly inhibited two other tyrosine kinases tested, KDR and src (IC50: 800 and 1400 nM). HKI-272 repressed the proliferation of a mouse fibroblast cell line (3T3) transfected with the HER-2 oncogene (3T3/neu) (IC50: 3 nM). HKI-272 also inhibited two other HER-2-overexpressing breast cancer cell lines, SK-Br-3, and BT474 (IC50: 2 nM). HKI-272 inhibited proliferation of the epidermal carcinoma cell line, A431, that overexpresses EGFR (IC50: 81 nM) [1]. Ba/F3 cells expressing EGFRvIII mutants are highly sensitive to HKI-272, (IC50: 9.4 nM), as are Ba/F3 cells expressing EGFR-L858R (IC50: 3.5 nM); EGFR-L858R-T790M-expressing cells are also sensitive to HKI-272 (IC50: 180 nM) [2].
体内活性 HKI-272 reduced tumor growth in a dose-dependent manner when administered orally between 20 mg/kg/day (53% inhibition, day 21) and 80 mg/kg/day (98% inhibition). In a second independent test, HKI-272 showed antitumor effects between 10 mg/kg/day (34% inhibition, day 14) and 40 mg/kg/day (98% inhibition). In xenografts of BT474, HKI-272 treatment repressed tumor growth when administered to animals between 10 mg/kg/day (67% inhibition, day 28) and 40 mg/kg/day (93% inhibition). Phosphorylation of HER-2 was inhibited by 84% within 1 h of administration with HKI-272 (40 mg/kg). Inhibition was sustained at 6 h (97%) and decreased to 43% over 24 h [1]. The three HKI-272 (50 mg/kg, p.o.)-treated mice experienced a more substantial tumor response, an average 88% reduction in tumor volume. Decrease of both total EGFRvIII and phospho-EGFR levels was observed after 1 week of HKI-272 treatment [2].
激酶实验 Activity of HER-2 and EGFR cytoplasmic domains was measured by an autophosphorylation assay using time-resolved fluorometry. Compounds were prepared as 10 mg/ml stocks in DMSO and diluted in 25 mm HEPES (pH 7.5; 0.002 ng/ml–20 μg/ml). Enzyme [diluted in 100 mm HEPES (pH 7.5) and 50% glycerol] was incubated with inhibitor in 4 mm HEPES (pH 7.5), 0.4 mm MnCl2, 20 μm sodium vanadate, and 0.2 mm DTT for 15 min at room temperature in 96-well ELISA plates. The kinase reaction was initiated by the addition of 40 μm ATP and 20 mm MgCl2 and allowed to proceed for 1 h at room temperature. Plates were washed, and phosphorylation was detected using Europium-labeled anti-phospho-tyrosine antibodies (15 ng/well). After washing and enhancement steps according to the manufacturer's recommendations, signal was detected using a Victor^2 fluorescence reader (excitation wavelength 340 nm, emission wavelength 615 nm). The concentration of compound that inhibited receptor phosphorylation by 50% (IC50) was calculated from inhibition curves [1].
细胞实验 Cells were plated in 96-well tissue culture plates (3T3, 3T3/neu, 5000 cells/well; A431, SK-Br-3, BT474, MDA-MB-435, and SW620, 10,000 cells/well). The following day, dilutions of compound (0.5 ng/ml–5 μg/ml) were added, and cells were cultured for 2 days (6 days for BT474). Cell proliferation was determined using sulforhodamine B, a protein binding dye. Briefly, cells were fixed with 10% trichloroacetic acid and washed extensively with water. Cells were then stained with 0.1% sulforhodamine B and washed in 5% acetic acid. Protein-associated dye was solubilized in 10 mm Tris, and absorbance was measured at 450 nm (Victor^2). Inhibition of cell proliferation was calculated using the formula: percentage of inhibition = 100 ? 100 (Td ? To/Tc ? To), where Td is the absorbance of drug-treated cells, Tc is the absorbance of untreated cells, and To is the absorbance at the time of drug addition. To values were determined by plating cells separately and fixing them at the time of drug addition. The concentration of compound which inhibits cell proliferation by 50% (IC50) was determined from inhibition curves [1].
动物实验 Athymic female nude mice (5 animals/group) were implanted s.c. with BT474 tumor fragments (~30 mm^3). When tumors reached 200–300 mg, animals were given a single oral dose (40 mg/kg) of HKI-272 in pH 2.0 water. Tumors from control and treated animals were excised at 1, 3, 6, and 24 h and minced. Tumor fragments were suspended in 10 mm Tris (pH 7.5), 5 mm EDTA, 150 mm NaCl, 1% Triton X-100, 1% sodium deoxycholate, 0.1% SDS, 1 mm phenylmethylsulfonyl fluoride, 10 μg/ml pepstatin, 10 μg/ml leupeptin, 10 μg/ml aprotinin, 2 mm sodium vanadate, and 100 mm sodium fluoride and lysed by homogenization on ice with a polytron. After clarification by centrifugation, protein concentration in lysates was estimated using the Bio-Rad DC protein assay. Sixty μg of lysate pooled from each group were analyzed by SDS-PAGE and immunoblotting with phospho-tyrosine-specific antibodies. Pooled extracts were also immunoprecipitated using 4 μg of anti-HER-2 antibodies for 1 h at 4°C. Immune complexes were collected on protein A-agarose, washed, and analyzed by immunoblotting using phospho-tyrosine-specific antibodies. Extracts from individual tumors were analyzed to determine variability between animals [1].
别名 HKI-272, 来那替尼
分子量 557.04
分子式 C30H29ClN6O3
CAS No. 698387-09-6

存储

Powder: -20°C for 3 years | In solvent: -80°C for 1 year

溶解度

H2O: < 1 mg/mL (insoluble or slightly soluble)

Ethanol: < 1 mg/mL (insoluble or slightly soluble)

DMSO: 5 mg/mL (8.9 mM), Sonification is recommended

溶液配制表

可选溶剂 浓度 体积 质量 1 mg 5 mg 10 mg 25 mg
DMSO 1 mM 1.7952 mL 8.976 mL 17.952 mL 44.8801 mL
5 mM 0.359 mL 1.7952 mL 3.5904 mL 8.976 mL

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参考文献

1. Rabindran SK, et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res, 2004, 64(11), 3958-3965. 2. Ji H, et al. Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7817-22.

文献引用

1. Qiu J, Jiang T, Gong Y, et al. Neratinib Exerts Dual Effects on Cartilage Degradation and Osteoclast Production in Osteoarthritis by Inhibiting the Activation of the Mapk/Nf-Κb Signaling Pathways. Biochemical Pharmacology. 2022 Nov;205:115155.
(S)-Afatinib Sophocarpine Endoxifen (Z-isomer) AG1557 BMS 599626 2HCl (873837-23-1(HCl)) SU5204 Epertinib BI-4142

相关化合物库

该产品包含在如下化合物库中:
酪氨酸激酶分子库 抗癌活性化合物库 抗癌药物库 高选择性抑制剂库 抗癌上市药物库 抗癌临床化合物库 经典已知活性库 共价抑制剂库 抗卵巢癌化合物库 抗前列腺癌化合物库

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请在以下方框中输入您的动物实验信息后点击计算,可以得到母液配置方法和体内配方的制备方法: 比如您的给药剂量是10 mg/kg,每只动物体重20 g,给药体积100 μL,一共给药动物10 只,您使用的配方为5% DMSO+30% PEG300+5% Tween 80+60% ddH2O。那么您的工作液浓度为2 mg/mL。

母液配置方法:2 mg 药物溶于 50 μL DMSO (母液浓度为 40 mg/mL), 如您需要配置的浓度超过该产品的溶解度,请先与我们联系。

体内配方的制备方法:取 50 μL DMSO 主液,加入 300 μL PEG300, 混匀澄清,再加 50 μL Tween 80,混匀澄清,再加 600 μL ddH2O, 混匀澄清。

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技术支持

您可能有的问题的答案可以在抑制剂处理说明中找到,包括如何准备库存溶液,如何存储产品,以及基于细胞的分析和动物实验需要特别注意的问题。

Keywords

Neratinib 698387-09-6 Angiogenesis JAK/STAT signaling Tyrosine Kinase/Adaptors EGFR HER A431 solid tumors inhibit HKI-272 gastric cancer non–small-cell lung cancer ErbB-1 HKI272 Inhibitor BT474 HER1 HKI 272 Epidermal growth factor receptor breast cancer 来那替尼 inhibitor

 

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