Tofacitinib (CP-690550,Tasocitinib)
(Synonyms: 托法替尼; Tasocitinib; CP-690550) 目录号 : GC16828
Tofacitinib (CP-690550,Tasocitinib)是一种Janus激酶（JAK）抑制剂，用于治疗类风湿关节炎、银屑病关节炎、强直性脊柱炎、多关节病程青少年特发性关节炎和溃疡性结肠炎。
Cas No.:477600-75-2
Sample solution is provided at 25 µL, 10mM.
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Tofacitinib (CP-690550,Tasocitinib) is a Janus kinase (JAK) inhibitor for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular course juvenile idiopathic arthritis, and ulcerative colitis treatment[1]. Tofacitinib targets the JAK-STAT pathway by inhibiting Janus kinase 1 (JAK1), Janus kinase 2, and Janus kinase 3 (JAK 3), impacting DNA transcription[2]. Tofacitinib interacts with all JAKs at the ATP-binding site at residue 839–1045 in JAK1, 839–1000 in JAK2, and 815–990 in JAK3 via electrostatic attraction, hydrogen bond formation, and in particular van der Waals interaction, and the Tofacitinib inhibits JAKs with an IC50 value of 3.3nM, 2.8nM, 19nM and 323nM for JAK1, JAK2, Tyk2 and JAK3 respectively[3].
In vitro, Tofacitinib (50nM; overnight) supresses natural killer cells to prolong amyotrophic lateral sclerosis (ALS) progression[4]. Tofacitinib (30μM, 60μM and 90μM; 4h) promotes functional recovery after spinal cord injury by regulating microglial polarization via JAK/STAT signaling pathway[5]. Tofacitinib (50μM; 3h) rescues intestinal barrier defects caused by disrupted epithelial-macrophage interactions[6].
In vivo, Tofacitinib (10mg/kg/day; 5-6 weeks; administrate with drinking water) fails to prevent T cell transfer colitis in mice[7]. Tofacitinib (10, 30, and 100mg/kg; 2 weeks; oral administration) enhances remyelination and improves myelin integrity in cuprizone-induced mice[8].
References:
[1] Berekmeri, Anna et al. “Tofacitinib for the treatment of psoriasis and psoriatic arthritis.” *Expert review of clinical immunology* vol. 14,9 (2018): 719-730. doi:10.1080/1744666X.2018.1512404
[2] Palmroth, Maaria et al. “Tofacitinib Suppresses Several JAK-STAT Pathways in Rheumatoid Arthritis *In Vivo* and Baseline Signaling Profile Associates With Treatment Response.” *Frontiers in immunology* vol. 12 738481. 24 Sep. 2021, doi:10.3389/fimmu.2021.738481
[3] Furumoto, Yasuko, and Massimo Gadina. “The arrival of JAK inhibitors: advancing the treatment of immune and hematologic disorders.” BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy vol. 27,5 (2013): 431-8. doi:10.1007/s40259-013-0040-7
[4] Figueroa-Romero, Claudia et al. “Tofacitinib Suppresses Natural Killer Cells *In Vitro* and *In Vivo*: Implications for Amyotrophic Lateral Sclerosis.” *Frontiers in immunology* vol. 13 773288. 7 Feb. 2022, doi:10.3389/fimmu.2022.773288
[5] Ma, Hongdao et al. “Tofacitinib Promotes Functional Recovery after Spinal Cord Injury by Regulating Microglial Polarization via JAK/STAT Signaling Pathway.” *International journal of biological sciences* vol. 19,15 4865-4882. 11 Sep. 2023, doi:10.7150/ijbs.84564
[6] Spalinger, Marianne R et al. “The JAK Inhibitor Tofacitinib Rescues Intestinal Barrier Defects Caused by Disrupted Epithelial-macrophage Interactions.” *Journal of Crohn's & colitis* vol. 15,3 (2021): 471-484. doi:10.1093/ecco-jcc/jjaa182
[7] Subramanyam, Sudheendra Hebbar et al. “Tofacitinib fails to prevent T cell transfer colitis in mice but ameliorates disease activity.” *Scientific reports* vol. 13,1 3762. 7 Mar. 2023, doi:10.1038/s41598-023-30616-w
[8] Günaydın, Caner et al. “Tofacitinib enhances remyelination and improves myelin integrity in cuprizone-induced mice.” *Immunopharmacology and immunotoxicology* vol. 43,6 (2021): 790-798. doi:10.1080/08923973.2021.1986063
Tofacitinib (CP-690550,Tasocitinib)是一种Janus激酶（JAK）抑制剂，用于治疗类风湿关节炎、银屑病关节炎、强直性脊柱炎、多关节病程青少年特发性关节炎和溃疡性结肠炎[1]。Tofacitinib通过抑制Janus kinase 1 （JAK1）、Janus kinase 2和Janus kinase 3 （JAK 3）靶向JAK- stat通路，影响DNA转录[2]。Tofacitinib与JAK1中839-1045位、JAK2中839-1000位和JAK3中815-990位的ATP结合位点上的所有JAK通过静电吸引、氢键形成，特别是范德瓦尔斯相互作用相互作用，Tofacitinib与JAK1, JAK2, Tyk2 and JAK3的IC50分别为3.3nM, 2.8nM, 19nM and 323nM[3]。
在体外，Tofacitinib(50nM；过夜)抑制自然杀伤细胞（NK-92 NK cell line）延长肌萎缩性侧索硬化症（ALS）的进展[4]。Tofacitinib（30μM、60μM和90μM；4h)通过JAK/STAT信号通路调控小胶质细胞极化，促进脊髓损伤后功能恢复[5]。Tofacitinib(50μM；3h)可修复由上皮-巨噬细胞相互作用中断引起的肠屏障缺陷[6]。
在体内，Tofacitinib(10mg/kg/天；5 - 6周；随水口服给药）在小鼠中不能预防T细胞转移性结肠炎[7]。Tofacitinib（10、30和100mg/kg；2周；口服给药)可增强cuprizone诱导小鼠的髓鞘再生和髓鞘完整性改善[8]。
| Cell experiment [1]: | |
Cell lines | NK-92 NK cell line |
Preparation Method | NK-92 cells were cultured using two IL-15/Tofacitinib paradigms. NK-92 cells were cultured for two hours with 2.33nM IL-15 in serum-free NK media prior to overnight treatment with 50nM Tofacitinib. NK-92 cells were cultured overnight with 50nM Tofacitinib in serum-free NK media prior to two-hour culture with 2.33nM IL-15. 50nM concentration of Tofacitinib was used based on previous in vitro immune studies. For each treatment paradigm, three groups of NK-92 cells were generated: cells receiving no IL-15 and no Tofacitinib (Unstimulated), cells receiving only IL-15 (Stimulated) or cells receiving IL-15 stimulation and Tofacitinib treatment (Treated). NK-92 cells were then collected, washed, and analyzed for STAT1 phosphorylation (P-STAT), cytotoxicity towards K-562 cells, granzyme B and perforin expression, or cytokine gene expression. |
Reaction Conditions | 50nM; overnight |
Applications | Tofacitinib suppressed IL-15-induced activation as measured by STAT1 phosphorylation, cytotoxicity, pro-inflammatory gene expression, and pro-inflammatory cytokine secretion in both an NK cell line and primary NK cells. |
| Animal experiment [2]: | |
Animal models | 8-12 week old C57BL/6 mice |
Preparation Method | For soluble Tofacitinib treatment, mice received of Tofacitinib or 0.2mg/ml dissolved in drinking water resulting in a dosage of 40mg/kg/day of Tofacitinib until end of experiments. |
Dosage form | 40mg/kg/day; 5–6 weeks; administrate with drinking water |
Applications | Treatment with Tofacitinib immediately after transfer resulted in an enhanced expansion of CD4+ T cells and did not prevent occurrence of colitis, treatment after start of symptoms of colitis ameliorated disease activity on a clinical basis and in histological analyses. |
References: | |
| Cas No. | 477600-75-2 | SDF | |
| 别名 | 托法替尼; Tasocitinib; CP-690550 | ||
| 化学名 | 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile | ||
| Canonical SMILES | CC1CCN(CC1N(C)C2=NC=NC3=C2C=CN3)C(=O)CC#N | ||
| 分子式 | C16H20N6O | 分子量 | 312.37 |
| 溶解度 | ≥ 15.6 mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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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 |
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动物平均体重 | g | |
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动物数量 | 只 |
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