Filgotinib (GLPG0634) 是首个选择性的 JAK 抑制剂，对 JAK1，JAK2，JAK3 和 TYK2 的IC50值分别为10 nM，28 nM，810 nM 和 116 nM。
别名：GLPG0634
Filgotinib (GLPG0634) is an orally-available, selective inhibitor of JAK1 (Janus kinase 1) for the treatment of rheumatoid arthritis and potentially other inflammatory diseases. Filgotinib (GLPG0634) dose-dependently inhibited Th1 and Th2 differentiation and to a lesser extent the differentiation of Th17 cells in vitro. GLPG0634 was well exposed in rodents upon oral dosing, and exposure levels correlated with repression of Mx2 expression in leukocytes. The JAK1 selective inhibitor GLPG0634 (Filgotinib) is a promising novel therapeutic with potential for oral treatment of rheumatoid arthritis and possibly other immune-inflammatory diseases. Filgotinib (GLPG0634) is currently in a Phase 2 study in Crohn's disease.
Front Cell Dev Biol. 2021 Apr 15;9:665869.
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数据来源 | Front Cell Dev Biol (2021). Figure 6. Filgotinib (Abmole Bioscience, Houston, USA) |
| 方法 | cell culture | |
| 细胞系/动物模型 | The TNBC cell lines MDA-MB-231 and MDA-MB-468 | |
| 浓度 | 1 µM | |
| 处理时间 | - | |
| 实验结果 | Filgotinib (JAK1-STAT1 inhibitor, 1 µM) abrogated SIRT1 expression in the CTRL group, while IFN-γ (JAK1-STAT1 agonist, 10 µg/mL) promoted SIRT1 expression in the Co-CM1 group |
| 体外实验* | |
|---|---|
| 细胞系 | T cells |
| 方法 | T cell differentiation studies. PBMCs were isolated from buffy coats of healthy donors (Blood Transfusion Center, Red Cross, Leuven, Belgium) using density gradient centrifugation on Lymphoprep. Naive CD4+ T cells were further isolated by depletion of non–T helper and memory CD4+ T cells using a naive CD4+ T cell isolation kit II (Miltenyi Biotec). Isolated naive CD4+ T cells were stimulated with plate-bound anti-CD3 (3 μg/ml) and anti-CD28 (5 μg/ml) Abs in the presence of cytokines that drive differentiation into Th1, Th2, or Th17 Th subsets. For Th1 cell polarization, cells were cultured in the presence of 10 μg/ml anti–IL-4 Ab (MAB204; R&D Systems), 10 ng/ml IL-2 (R&D Systems), and 10 ng/ml IL-12 (R&D Systems) (17). For Th2 cell polarization, cells were cultured in the presence of 10 μg/ml anti–IFN-γ Ab (Becton Dickinson), 25 ng/ml IL-4 (R&D Systems), and 10 ng/ml IL-2 (17). For Th17 cell polarization, a mix of the following cytokines was used: 10 ng/ml IL-6 (R&D Systems), 10 ng/ml IL-1β (R&D Systems), 1 ng/ml TGF-β (PeproTech), and 100 ng/ml IL-23 (R&D Systems) (18). To monitor effects of compounds on T cell differentiation, compounds were added at indicated concentrations at the start of T cell differentiation. After 5 d, RNA was extracted using an RNeasy Mini kit (Qiagen), reverse transcribed, and the extent of Th subset differentiation was monitored by determining expression of IFN-γ (Th1 marker), IL-13 (Th2 marker), or IL-17F (Th17 marker) using real-time PCR on the ViiA7 thermocycler with predesigned TaqMan Assay-on-Demand gene expression primer/probe sets (Applied Biosystems). Gene expression was normalized to 18S and expressed as ΔCt values, with ΔCt = Ctgene − Ct18S or expressed as relative mRNA level of specific gene expression as obtained using the 2−ΔCt method. |
| 浓度 | 10, 1, 0.1 or 0 μM |
| 处理时间 | 5 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 | therapeutic rat CIA model |
| 配制 | 0.05 M acetic acid |
| 剂量 | 50 mg/kg twice daily for 14 d |
| 给药处理 | oral |
*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 | 425.5 |
| 分子式 | C21H23N5O3S |
| CAS号 | 1206161-97-8 |
| 溶解性（25°C） | DMSO 20 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 | 2.3502 mL | 11.7509 mL | 23.5018 mL |
| 5 mM | 0.47 mL | 2.3502 mL | 4.7004 mL |
| 10 mM | 0.235 mL | 1.1751 mL | 2.3502 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JAK产品 |
|---|
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A-005 是一款潜在首创的（first-in-class），可渗透大脑的TYK2别构抑制剂，可用于神经炎症和神经退行性疾病的相关研究。 |
| Tyrosine Protein Kinase JAK 2 (Phospho-Tyr8, 9)
Tyrosine Protein Kinase JAK 2 (Phospho-Tyr8, 9) 是小鼠JAK2 对应的475到491氨基酸序列的多肽。 |
| JAK2/FLT3-IN-1 TFA
JAK2/FLT3-IN-1 (TFA) 是一种口服有效的双重 JAK2/FLT3 抑制剂，对 JAK2，FLT3，JAK1 和 JAK3 的 IC50 分别为 0.7 nM，4 nM，26 nM 和 39 nM。 |
| ZT55
ZT55 是一种口服有效并具有高选择性的 JAK2 抑制剂，其 IC50 值为 0.031 μM。 |
| ZM39923
ZM39923 是一种 JAK3 抑制剂， pIC50 值为 7.1；ZM39923 同时可抑制组织型转谷氨酞胺酶 (TGM2) 的活性，IC50 值为 10 nM。 |
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