Tofacitinib (CP-690550,Tasocitinib)是一种新型的，具有口服活性的JAK3抑制剂，IC50为1 nM，作用于JAK2和JAK1选择性低20到100倍，可用于炎症性肠病（IBD），斑块状银屑病和斑秃的相关研究。
别名：CP-690550, Tasocitinib
Tofacitinib (CP-690550,Tasocitinib)是一种新型JAK3抑制剂，IC50为1 nM，作用于JAK2和JAK1选择性低20到100倍。CP-690550 是特定的口服JAK3抑制剂, 作用于JAK2 和 JAK1,效果分别低20和100倍。CP-690550 对30种其他激酶没有作用效果，平均IC50 > 3000 nM。CP-690,550抑制IL-2诱导的增殖，比作用于GM-CSF诱导的增殖效果强30倍。
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Arch Dermatol Res. 2018 Oct 5.
Effect of tofacitinib on the expression of noggin/BMP-4 and hair growth stimulation in mice
Arch Dermatol Res. 2017 Sep 7.
TJPS. 2017;41 (Supplement Issue): 225-228.
Topical tofacitinib reduce expression of BMP-4 in mouse hair follicle
Sci Adv. 2015 Oct 23.
Pharmacologic inhibition of JAK-STAT signaling promotes hair growth.
Nat Med. 2014 Sep;20(9):1043-9.
Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.
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数据来源 | Archives of Dermatological Research (2018). Figure 2. Tofacitinib (Abmole Bioscience, Houston, USA) |
| 方法 | i.v. | |
| 细胞系/动物模型 | C57BL/6 mice | |
| 浓度 | concentration of 2% | |
| 处理时间 | 21 consecutive days | |
| 实验结果 | The length of the hair infundibulum on the 21st day of the experiment was higher in groups treated topically with tofacitinib. |
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数据来源 | Archives of Dermatological Research (2018). Figure 1. Tofacitinib (Abmole Bioscience, Houston, USA) |
| 方法 | i.v. | |
| 细胞系/动物模型 | C57BL/6 mice | |
| 浓度 | concentration of 2% | |
| 处理时间 | 21 consecutive days | |
| 实验结果 | In mice treated topically with tofacitinib, 84.7% of hairs were in the anagen phase (n=72), 10.6% were in the catagen phase (n = 9), and 4.7% were in the telogen phase (n=4), where the follicles in the late anagen were located in the deep dermis and hypodermis, and follicles in the early anagen were located in the superficial dermis. |
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数据来源 | US Patent 9730877B2 (2017). Figure 32. Tofacitinib (Abmole Bioscience) |
| 方法 | oral | |
| 细胞系/动物模型 | mice | |
| 浓度 | 15 mg/kg/day | |
| 处理时间 | 12 weeks | |
| 实验结果 | None of the treated mice developed alopecia areata or cutaneous lymphadenopathy, whereas untreated mice manifested both AA and associated cutaneous lymphadenopathy |
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数据来源 | TJPS (2017). Figure 2. Tofacitinib (Abmole Bioscience, Houston, TX, USA) |
| 方法 | qRT-PCR | |
| 细胞系/动物模型 | mice hair follicle | |
| 浓度 | 2% concentration | |
| 处理时间 | 21 days | |
| 实验结果 | We investigate the expression of BMP4 which known to be an inhibitory molecule for onset of anagen entry. Quantitative real-time reverse transcription-PCR analysis showed decrease expression of BMP4 in tofacitinib treated group compare to DMSO-treated group (p-value 0.003). |
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数据来源 | TJPS (2017). Figure 1. Tofacitinib (Abmole Bioscience, Houston, TX, USA) |
| 方法 | Inject | |
| 细胞系/动物模型 | C57BL/6 male mice | |
| 浓度 | 2% concentration | |
| 处理时间 | 21 days | |
| 实验结果 | We examined the effect of topical tofacitinib on hair growth in mice tissue, tofacitinib-treated group has shown denser in thickness and length of hair follicle compared to vehicle (Figure 1A). Histology, tofacitinib treated group has shown increased in anagen hair follicle compared to vehicle (Figure 1B). |
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数据来源 | Arch Dermatol Res (2017). Figure 6. Tofacitinib (Abmole Bioscience, Texas, USA) |
| 方法 | HE stain | |
| 细胞系/动物模型 | Mice | |
| 浓度 | dissolved in DMSO to create a 2% concentration | |
| 处理时间 | 21 day | |
| 实验结果 | Tofacitinib-treated mice showed less infiltration of inflammatory cells relative to minoxidil-treated mice. In the DMSO-treated group, infiltration of several inflammatory cells infiltration was observed, while fewer inflammatory cells were observed in the ethanol-treated group. |
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数据来源 | Arch Dermatol Res (2017). Figure 5. Tofacitinib (Abmole Bioscience, Texas, USA) |
| 方法 | HE stain | |
| 细胞系/动物模型 | Mice | |
| 浓度 | dissolved in DMSO to create a 2% concentration | |
| 处理时间 | 21 day | |
| 实验结果 | More newly formed capillaries were observed in the tofacitinib-treated group than in the minoxidil- and controltreated groups, although some completely formed capillaries were observed in the minoxidil- and DMSO-treated groups. |
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数据来源 | Arch Dermatol Res (2017). Figure 4. Tofacitinib (Abmole Bioscience, Texas, USA) |
| 方法 | HE stain | |
| 细胞系/动物模型 | Mice | |
| 浓度 | dissolved in DMSO to create a 2% concentration | |
| 处理时间 | 21 day | |
| 实验结果 | "At the end of the experiment, mostly anagen hairs were observed in the tofacitinib-treated group, whereas mostly catagen and anagen hairs were observed in minoxidil- and DMSO-treated groups." |
. ruxolitinib, figure 4..jpg) |
数据来源 | Science Advance (2015). Ruxolitinib, Figure 4. (AbMole Bioscience) |
| 方法 | Patch assay with DP spheres | |
| 细胞系/动物模型 | DP cells | |
| 浓度 | 400 nM | |
| 处理时间 | ||
| 实验结果 | In the region including genes thatwere upregulated by ruxolitinib treatment but down-regulated by tofacitinib treatment, we identified proapoptotic genes such as BAX, BCL2L11, and CASP12 (region 2). |
. ruxolitinib, figure 3..jpg) |
数据来源 | Science Advance (2015). Ruxolitinib, Figure 3. (AbMole Bioscience) |
| 方法 | Human HF organ culture assay | |
| 细胞系/动物模型 | human HFs | |
| 浓度 | 400 nM | |
| 处理时间 | ||
| 实验结果 | We found that treatment with JAK inhibitors significantly increased the length of hair shafts when treatedwith ruxolitinib and tofacitinib, indicating a positive effect on the rate of hair elongation (P = 0.023 and P = 0.025 for tofacitinib and ruxolitinib, respectively). |
. ruxolitinib, figure 1..jpg) |
数据来源 | Science Advance (2015). Ruxolitinib, Figure 1. (AbMole Bioscience) |
| 方法 | Fourmice were treated with control (half of the back skin) and ruxolitinib (half of the back skin) and four mice were treated with control (half of the back skin) and tofacitinib (half of the back skin). | |
| 细胞系/动物模型 | ||
| 浓度 | ||
| 处理时间 | ||
| 实验结果 | Indeed, ~90% of 8.5-week-old mice treated with ruxolitinib or tofacitinib for 5 days displayed skin darkening and hair growth within 10 days of starting treatment, whereas no hair growth was evident in control-treated mice (P < 0.0001 for ruxolitinib treatment and P = 0.04 for tofacitinib treatment). Ruxolitinib treatment enriched for the mTOR (mammalian target of rapamycin) and NFkB (nuclear factor kB) pathways, both previously shown to be involved in hair cycle regulation, whereas tofacitinib treatment enriched for pathways involved in cell motility and migration, such as Rho and integrin signaling. |
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数据来源 | Nature medicine (2014). Figure 1. tofacitinib (Abmole) |
| 方法 | Flow cytometric analysis, Immunohistochemistry and immunofluorescence | |
| 细胞系/动物模型 | ||
| 浓度 | 15 mg/kg/day | |
| 处理时间 | 12 weeks | |
| 实验结果 | "We observed complete hair regrowth within 12 weeks following topical therapy. Topical therapy was associated with a markedly reduced proportion of CD8+NKG2D+T cells in the treated skin and lymph node, normalization of the ALADIN transcriptional signature, reversal of histological markers of disease. " |
-1.jpg) |
数据来源 | Nature medicine (2014). Figure 3. tofacitinib (Abmole) |
| 方法 | Flow cytometric analysis, Immunohistochemistry and immunofluorescence | |
| 细胞系/动物模型 | ||
| 浓度 | 15 mg/kg/day | |
| 处理时间 | 12 weeks | |
| 实验结果 | we systemically administered tofacitinib at the time of grafting and found that they prevented the development of AA and the expansion of CD8+NKG2D+ T cells in all grafted recipients. The skin of mice treated with either drug showed no histological signs of inflammation. Global transcriptional analysis of whole-skin biopsies showed that both drugs also blocked the dermal inflammatory signature, as measured by Alopecia Areata Disease Activity Index. |
-2.jpg) |
数据来源 | Nature medicine (2014). Figure 1. JAK3i tofacitinib (Abmole) |
| 方法 | grafted C3H/HeJ mice | |
| 细胞系/动物模型 | CD8+NKG2D+ T cells | |
| 浓度 | 15 mg/kg/day | |
| 处理时间 | 12 weeks | |
| 实验结果 | we observed complete hair regrowth within 12 weeks following topical therapy. Topical therapy was associated with a markedly reduced proportion of CD8+NKG2D+ T cells in the treated skin and lymph node, normalization of the ALADIN transcriptional signature, reversal of histological markers of disease. |
-1.jpg) |
数据来源 | Nature medicine (2014). Figure 1. JAK3i tofacitinib (Abmole) |
| 方法 | grafted C3H/HeJ mice | |
| 细胞系/动物模型 | CD8+NKG2D+ T cells | |
| 浓度 | 15 mg/kg/day | |
| 处理时间 | 12 weeks | |
| 实验结果 | Global transcriptional analysis of whole-skin biopsies showed that both drugs also blocked the dermal inflammatory signature, as measured by Alopecia Areata Disease Activity Index |
| 体外实验* | |
|---|---|
| 细胞系 | cytokine-dependent NK92 cell line |
| 方法 | (A) After cytokine starvation for 24 hours, NK92 cells were stimulated by the addition of human IL-2 for 48 hours with and without the addition of serially increasing concentrations of tofacitinib. 3H-thymidine was added during the last 6 hours of the cultures. Cells were then harvested and analyzed for 3H-thymidine incorporation. (B) Cytokine-starved NK92 cells were stimulated with human IL-2, combined IL-6/IL- 6R, or IL-12 for 48 hours with and without serially increasing concentrations of tofacitinib. (C) The NK92 cells were treated as those in panel B with and without a single 50nM dose of tofacitinib. Data are presented as means ±SD (A-C) and are representative of 3 independent experiments. (D) After cytokine starvation for 24 hours, NK92 cells were stimulated with 30 ng/mL of IL-2, 100 ng/mL of combined IL-6/IL-6R, or 100 ng/mL of IL-12 for 1 hour with and without the addition of tofacitinib. The cell lysates were immunoblotted with an anti–phospho-STAT5 monoclonal antibody and an anti-STAT5 antibody. ß-Actin was used as an input control. Data are representative of 3 independent experiments. |
| 浓度 | 0~400 nM |
| 处理时间 | 48 h |
*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 | IL-15–transgenic CD8 T-cell leukemia–bearing mice |
| 配制 | dissolved in polyethylene glycol 300 (PEG300; VWR Scientific Products) |
| 剂量 | 50 mg/mL |
| 给药处理 | continuously administered via a subcutaneous mini-osmotic pump (ALZET) |
*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 | 312.37 |
| 分子式 | C16H20N6O |
| CAS号 | 477600-75-2 |
| 溶解性（25°C） | DMSO ≥60 mg/mL |
| 储存条件 | -20°C, sealed |
| 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 | 3.2013 mL | 16.0067 mL | 32.0133 mL |
| 5 mM | 0.6403 mL | 3.2013 mL | 6.4027 mL |
| 10 mM | 0.3201 mL | 1.6007 mL | 3.2013 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。
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