PF-06700841 P-Tosylate is a potent dual Janus kinase 1 (JAK1) and TYK2 inhibitor with IC50 values of 17nM and 23nM, respectively [1]. PF-06700841 P-Tosylate inhibits JAK-dependent signaling at multiple points in the pathogenic cycle, including keratinocyte signaling, maintenance of inflammatory T-cell infiltrate, and direct inhibition of TYK2-dependent IL-23 signaling[2]. PF-06700841 P-Tosylate has been widely used to attenuate both cutaneous and muscular inflammation in different models[3].
In vitro, PF-06700841 P-Tosylate pretreatment at 10µM for 1h inhibited IFNγ-induced nitrite production and cytokine transcription in Raw264.7 cells[4]. PF-06700841 P-Tosylate (20nM) treatment for 24h significantly inhibited the proliferation, migration, and invasion effects of hyperin on HTR-8/SVneo cells[5].
In vivo, PF-06700841 P-Tosylate treatment via oral administration at a dose of 3mg/kg/day for 3 days significantly mitigated lipopolysaccharide (LPS)-induced neutrophil inflammation in mice[6]. Oral administration of PF-06700841 P-Tosylate at a dose of 30mg/kg/day for 3 consecutive days significantly alleviated disease severity in a rat model of adjuvant-induced arthritis (AIA)[7].
References:
[1] Li Y, Chen J, Bolinger A A, et al. Target-based small molecule drug discovery towards novel therapeutics for inflammatory bowel diseases[J]. Inflammatory bowel diseases, 2021, 27(Supplement_2): S38-S62.
[2] Page K M, Suarez-Farinas M, Suprun M, et al. Molecular and cellular responses to the TYK2/JAK1 inhibitor PF-06700841 reveal reduction of skin inflammation in plaque psoriasis[J]. Journal of Investigative Dermatology, 2020, 140(8): 1546-1555. e4.
[3] Krueger J G, McInnes I B, Blauvelt A. Tyrosine kinase 2 and Janus kinase‒signal transducer and activator of transcription signaling and inhibition in plaque psoriasis[J]. Journal of the American Academy of Dermatology, 2022, 86(1): 148-157.
[4] Romero-Ramírez L, García-Rama C, Mey J. Janus kinase inhibitor brepocitinib rescues myelin phagocytosis under inflammatory conditions: in vitro evidence from microglia and macrophage cell lines[J]. Molecular Neurobiology, 2024, 61(9): 6423-6434.
[5] Mu Z, Shen S, Tang L, et al. Hyperin promotes proliferation, migration, and invasion of HTR-8/SVneo trophoblast cells via activation of JAK1/STAT3 pathway in recurrent spontaneous abortions[J]. Heliyon, 2023, 9(1).
[6] Nayak B B, Bärnthaler T, Rajesh R, et al. Brepocitinib, a selective TYK2/JAK1 inhibitor, mitigates neutrophilic inflammation and glucocorticoid receptor-β expression in COPD[J]. American Journal of Physiology-Lung Cellular and Molecular Physiology, 2026.
[7] Fensome A, Ambler C M, Arnold E, et al. Dual inhibition of TYK2 and JAK1 for the treatment of autoimmune diseases: discovery of ((S)-2, 2-difluorocyclopropyl)((1 R, 5 S)-3-(2-((1-methyl-1 H-pyrazol-4-yl) amino) pyrimidin-4-yl)-3, 8-diazabicyclo [3.2. 1] octan-8-yl) methanone (PF-06700841)[J]. Journal of medicinal chemistry, 2018, 61(19): 8597-8612.
PF-06700841 P-Tosylate是一种强效的双重Janus激酶1（JAK1）和TYK2抑制剂，IC50值分别为17nM和23nM[1]。PF-06700841 P-Tosylate可在致病周期的多个节点抑制JAK依赖性信号传导，包括角质形成细胞信号传导、炎症性T细胞浸润的维持，以及直接抑制TYK2依赖性IL-23信号传导[2]。PF-06700841 P-Tosylate已被广泛用于减轻不同模型中的皮肤和肌肉炎症[3]。
在体外，使用10µM的PF-06700841 P-Tosylate预处理Raw264.7细胞1小时，抑制了IFNγ诱导的亚硝酸盐生成和细胞因子转录[4]。使用20nM的PF-06700841 P-Tosylate处理HTR-8/SVneo细胞24小时，显著抑制了hyperin对细胞的增殖、迁移和侵袭的效应 [5]。
在体内，每日口服给予3mg/kg剂量的PF-06700841 P-Tosylate，连续3天，显著减轻了脂多糖（LPS）诱导的小鼠中性粒细胞炎症[6]。连续3天每日口服给予30mg/kg剂量的PF-06700841 P-Tosylate，显著减轻了佐剂性关节炎（AIA）大鼠模型的疾病严重程度[7]。