Neratinib (HKI-272)是一种高度选择性的HER2和EGFR抑制剂，IC50分别为59 nM和92 nM；微弱抑制KDR和Src，对Akt，CDK1/2/4， IKK-2， MK-2， PDK1， c-Raf和c-Met没有显著的抑制作用。
别名：HKI-272
Neratinib (HKI-272)是一种高度选择性的HER2和EGFR抑制剂，IC50分别为59 nM和92 nM；微弱抑制KDR和Src，对Akt，CDK1/2/4， IKK-2， MK-2， PDK1， c-Raf和c-Met没有显著的抑制作用。Neratinib微弱抑制酪氨酸激酶KDR 和Src，IC50分别为0.8 μM 和 1.4 μM,与 HER-2相比，活性分别弱14和24倍。Neratinib 作用于其他丝-苏氨酸激酶如Akt, cyclin D1/cdk4, cyclin E/cdk2, cyclin B1/cdk1, IKK-2, MK-2, PDK1, c-Raf, 和Tpl-2，以及酪氨酸激酶c-Met没有活性。Neratinib选择性抑制转染 HER-2 (3T3/neu)的3T3细胞增殖,也抑制两种其他 HER-2-过表达的SK-Br-3和 BT474 cells细胞增殖，IC50为 2-3 nM,与未转染的3T3细胞及 EGFR-和 HER-2阴性的MDA-MB-435 和 SW620细胞相比，效果高230倍以上。
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ACS Chem Biol. 2016 May 20;11(5):1245-54.
Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors
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数据来源 | ACS Chem Biol (2016). Figure 5. Neratinib (Abmole Bioscience) |
| 方法 | FECH inhibition assay | |
| 细胞系/动物模型 | K562 Cells | |
| 浓度 | 1 μM | |
| 处理时间 | 6 days | |
| 实验结果 | In line with the Kd values obtained from kinobead experiments, Vemurafenib, CUDC 101, Cyc-116, Linsitinib, MK-2461, Neratinib, GSK-690693, and Crenolanib decreased FECH binding to the PPIX beads by 50% or more compared to the DMSO control. |
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数据来源 | ACS Chem Biol (2016). Figure 4. Neratinib (Abmole Bioscience) |
| 方法 | FECH inhibition assay | |
| 细胞系/动物模型 | K562 Cells | |
| 浓度 | 1 μM | |
| 处理时间 | 6 days | |
| 实验结果 | We then subjected MK-2461, Neratinib, and Linsitinib to the same assay (1 μM for 6 days), and each drug clearly led to reduced heme levels indicating inhibition of FECH activity in K562 cells with Neratinib showing the most potent effect (60% reduction). |
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数据来源 | ACS Chem Biol (2016). Figure 3. Neratinib (Abmole Bioscience) |
| 方法 | FECH binding | |
| 细胞系/动物模型 | K562 Cells | |
| 浓度 | ||
| 处理时间 | ||
| 实验结果 | The basis of this assay is that proteins bound to a drug molecule are stabilized against heat induced unfolding and aggregation, and the extent of this protection is dose dependent. |
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数据来源 | ACS Chem Biol (2016). Figure 2. Neratinib (Abmole Bioscience) |
| 方法 | FECH binding | |
| 细胞系/动物模型 | ||
| 浓度 | ||
| 处理时间 | ||
| 实验结果 | Figure 2b−f show the full dose response data for five selected inhibitors, and the complete set of these plots can be found in Supporting Information Figure S1 and Table S1. |
| 体外实验* | |
|---|---|
| 细胞系 | 3T3, 3T3/neu, A431, SK-Br-3, BT474, MDA-MB-435, and SW62 cells |
| 方法 | Cell Proliferation Assays. 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 (Sigma-Aldrich) and washed in 5% acetic acid. Protein-associated dye was solubilized in 10 mm Tris, and absorbance was measured at 450 nm (Victor2). 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. |
| 浓度 | 0.5 ng/ml-5 μg/ml |
| 处理时间 | 2 days |
*上述方法来自公开文献，仅供相同目的实验参考。如实验目的、材料、方法不同，请参考其他文献。
| 体内实验* | |
|---|---|
| 动物模型 | BT474, MCF-7, and SK-OV-3 tumour xenografts model in female athymic (nude) mice |
| 配制 | 0.5% methocellulose-0.4% polysorbate-80 (Tween 80) |
| 剂量 | 40 or 60mg/kg daily for 20 days |
| 给药处理 | oral gavage |
*上述方法来自公开文献，仅供相同目的实验参考。如实验目的、材料、方法不同，请参考其他文献。
| 分子量 | 557.04 |
| 分子式 | C30H29ClN6O3 |
| CAS号 | 698387-09-6 |
| 溶解性（25°C） | DMSO 8 mg/mL |
| 储存条件 |
粉末型式 -20°C 3年；4°C 2年 溶于溶剂 -80°C 6个月；-20°C 1个月 |
| 运输方式 | 冰袋运输，根据产品的不同，可能会有相应调整。 |
*下述溶液配置方法仅为基于分子量计算出的理论值。不同产品在配置溶液前，需考虑其在不同溶剂中的溶解度限制。
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.7952 mL | 8.976 mL | 17.952 mL |
| 5 mM | 0.359 mL | 1.7952 mL | 3.5904 mL |
| 10 mM | 0.1795 mL | 0.8976 mL | 1.7952 mL |
| 小鼠 | 大鼠 | 兔 | 豚鼠 | 仓鼠 | 狗 | |
| 重量 (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| 体表面积 (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km 系数 | 3 | 6 | 12 | 8 | 5 | 20 |
| 动物 A (mg/kg) = 动物 B (mg/kg) × | 动物 B的Km系数 |
| 动物 A的Km系数 |
例如，依据体表面积折算法，将化合物用于小鼠的剂量20 mg/kg 换算成大鼠的剂量，需要将20 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到化合物用于大鼠的等效剂量为10 mg/kg。
| 其他相关的EGFR/HER2产品 |
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BBT-207是一种可逆的、突变体特异性的 EGFR 抑制剂，具有抗肿瘤活性。 |
| VRN-11
VRN-11是一种 EGFR C797S 抑制剂。 |
| TRX-221
TRX-221是一种 EGFR C797S 抑制剂。 |
| TAS-3351
TAS-3351 是一种表皮生长因子受体 EGFR C797S 抑制剂。 |
| Larotinib mesylate hydrate
Larotinib mesylate hydrate 是一种有效的、广谱的、具有口服活性的酪氨酸激酶抑制剂 (TKI)，其以 EGFR 为主要靶点，IC50 为 0.6 nM。 |
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