Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Acta Pharmacol Sin. 2021 Oct;42(10):1653-1664. doi: 10.1038/s41401-020-00578-0. Epub 2021 Jan 13.
Rheumatoid arthritis (RA) is characterized by joint leukocyte infiltration, synovial inflammation and bone damage result from osteoclastogenesis. Bruton's tyrosine kinase (BTK) is a key regulator of B cell receptor (BCR) and Fc gamma receptor (FcγR) signaling involved in the pathobiology of RA and other autoimmune disorders. SOMCL-17-016 is a potent and selective tricyclic BTK inhibitor, structurally distinct from other known BTK inhibitors. In present study we investigated the therapeutic efficacy of SOMCL-17-016 in a mouse collagen-induced arthritis (CIA) model and underlying mechanisms. CIA mice were administered SOMCL-17-016 (6.25, 12.5, 25 mg·kg·d, ig), or ibrutinib (25 mg·kg·d, ig) or acalabrutinib (25 mg·kg·d, ig) for 15 days. We showed that oral administration of SOMCL-17-016 dose-dependently ameliorated arthritis severity and bone damage in CIA mice; it displayed a higher in vivo efficacy than ibrutinib and acalabrutinib at the corresponding dosage. We found that SOMCL-17-016 administration dose-dependently inhibited anti-IgM-induced proliferation and activation of B cells from CIA mice, and significantly decreased anti-IgM/anti-CD40-stimulated RANKL expression in memory B cells from RA patients. In RANKL/M-CSF-stimulated RAW264.7 cells, SOMCL-17-016 prevented osteoclast differentiation and abolished RANK-BTK-PLCγ2-NFATc1 signaling. In summary, this study demonstrates that SOMCL-17-016 presents distinguished therapeutic effects in the CIA model. SOMCL-17-016 exerts a dual inhibition of B cell function and osteoclastogenesis, suggesting that it to be a promising drug candidate for RA treatment.
类风湿关节炎（RA）的特征是关节白细胞浸润、滑膜炎症和破骨细胞生成导致的骨损伤。布鲁顿酪氨酸激酶（BTK）是 B 细胞受体（BCR）和 Fc 受体（FcγR）信号的关键调节剂，参与 RA 和其他自身免疫性疾病的病理生物学过程。SOMCL-17-016 是一种有效的、选择性的三环 BTK 抑制剂，与其他已知的 BTK 抑制剂在结构上不同。在本研究中，我们研究了 SOMCL-17-016 在小鼠胶原诱导关节炎（CIA）模型中的治疗效果及其潜在机制。CIA 小鼠给予 SOMCL-17-016（6.25、12.5、25mg·kg·d，ig）、伊布替尼（25mg·kg·d，ig）或阿卡替尼（25mg·kg·d，ig）治疗 15 天。结果表明，SOMCL-17-016 口服给药可剂量依赖性地改善 CIA 小鼠的关节炎严重程度和骨损伤；在相应剂量下，其体内疗效高于伊布替尼和阿卡替尼。我们发现，SOMCL-17-016 给药可剂量依赖性地抑制 CIA 小鼠抗 IgM 诱导的 B 细胞增殖和活化，并显著降低 RA 患者记忆 B 细胞中抗 IgM/抗 CD40 刺激的 RANKL 表达。在 RANKL/M-CSF 刺激的 RAW264.7 细胞中，SOMCL-17-016 可阻止破骨细胞分化并消除 RANK-BTK-PLCγ2-NFATc1 信号。综上所述，本研究表明 SOMCL-17-016 在 CIA 模型中具有显著的治疗效果。SOMCL-17-016 对 B 细胞功能和破骨细胞生成具有双重抑制作用，表明其可能成为治疗 RA 的有前途的候选药物。
