类风湿性关节炎（RA）是一种复杂的自身免疫性疾病，其特征是关节内免疫细胞的过度活化，导致炎症、骨退化和慢性疼痛。几十年来，抗肿瘤坏死因子（TNF）生物制剂阿达木单抗（Humira）、艾坦塞普（Enbrel）和英夫利昔单抗（Remicade）等前线免疫调节剂在许多患者中成功控制疾病进展。然而，随着时间的推移，患者对这些治疗变得难以应对，需要使用甲氨蝶呤、羟氯喹和皮质类固醇等传统且更有问题的疾病修复性抗风湿药物进行慢性病管理。由于大量患者在前线生物制剂治疗失败，仍存在一种未满足的需求，即寻找新的替代治疗靶点，以提高治疗RA的疗效和安全性。最近在这一领域的进展中，发现了在RA病理过程中起重要作用的新靶点，包括Janus激活激酶（JAK）和转化生长因子β激活激酶-1（TAK1）。尽管三种JAK信号通路抑制剂已获批用于治疗中度至重度活动性RA患者（对一种或多种抗TNF治疗无效），但目前尚无经FDA批准的TAK1治疗方法。我们最近发现了一种高度有效且选择性的口服可利用的TAK1抑制剂，这为作为治疗RA的新靶点的这种蛋白激酶的治疗潜力提供了见解。我们在这里展示了在脂多糖（LPS）刺激的THP-1细胞中托法替尼（Xeljanz；JAK1/3抑制剂）和HS-276（TAK1抑制剂）的不同细胞因子信号。此外，在胶原诱导的RA临床前小鼠模型中，托法替尼和HS-276均减轻了疾病活动评分和血清中的炎症细胞因子。总的来说，我们的结果阐述了JAK1/3和TAK1靶向治疗的不同细胞因子信号在体外和体内的作用，并表明选择性的TAK1抑制剂可能在RA治疗中提供更优越的治疗缓解效果，少发生不良事件。 © 2023 Eydis Bio, Inc and The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.

Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by hyperactive immune cells within the joints, which leads to inflammation, bone degeneration, and chronic pain. For several decades, frontline immunomodulators such as the anti-tumor necrosis factor (TNF) biologics adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade) have successfully managed disease progression for many patients. However, over time, patients become refractory to these treatments requiring chronic disease to be managed with conventional and more problematic disease modifying antirheumatic drugs such as methotrexate and hydroxychloroquine, and corticosteroids. Due to the large proportion of patients who continue to fail on frontline biologic therapies, there remains an unmet need to derive novel alternative targets with improved efficacy and safety profiles to treat RA. Recent advances in the field have defined novel targets that play important roles in RA pathology, including the Janus activated kinase (JAK) and transforming growth factor beta activated kinase-1 (TAK1). Although three inhibitors of the JAK signaling pathway have been approved for the treatment of moderately to severely active RA in patients who failed on one or more anti-TNFs, at present, no FDA approved TAK1 treatments exist. Our recent discovery of a highly potent and selective, orally bioavailable TAK1 inhibitor has provided insight into the therapeutic potential of this protein kinase as a novel target for RA. Here, we show the distinct cytokine signaling of tofacitnib (Xeljanz; JAK1/3 inhibitor) compared to HS-276 (TAK1 inhibitor) in lipopolysaccharide (LPS) challenged THP-1 cells. Furthermore, in the collagen induced arthritis pre-clinical mouse model of RA, both tofacintib and HS-276 attenuated disease activity score and inflammatory cytokines in the serum. Overall, our results delineate the distinct cytokine signaling of JAK1/3 and TAK1 targeted therapies in vitro and in vivo and suggest that selective TAK1 inhibitors may provide superior therapeutic relief in RA with fewer adverse events.© 2023 Eydis Bio, Inc and The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.