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]。