A novel tricyclic BTK inhibitor suppresses B cell responses and osteoclastic bone erosion in rheumatoid arthritis
A novel tricyclic BTK inhibitor suppresses B cell responses and osteoclastic bone erosion in rheumatoid arthritis
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一种新型三环 BTK 抑制剂可抑制类风湿性关节炎中的 B 细胞反应和破骨细胞骨侵蚀
DOI：
10.1038/s41401-020-00578-0
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发表时间：
2021-01-13
影响因子：
8.2
通讯作者：
Zuo, Jian-ping
中科院分区：
文献类型：
--
作者：
Liu, Yu-ting;Ding, Hui-hua;Zuo, Jian-ping
类风湿性关节炎（RA）是以关节白细胞浸润、滑膜炎症和破骨细胞生成引起的骨损伤为特征的疾病。布鲁顿酪氨酸激酶（BTK）是参与RA和其他自身免疫性疾病的病理生物学的B细胞受体（BCR）和Fc γ受体（Fc γ R）信号传导的关键调节剂。SOMCL-17-016是一种有效的选择性三环BTK抑制剂，在结构上不同于其他已知的BTK抑制剂。在本研究中，我们研究了SOMCL-17-016在小鼠胶原诱导关节炎（CIA）模型中的治疗功效及其潜在机制。对CIA小鼠施用SOMCL-17-016（6.25、12.5、25 mg.kg（-1）.d（-1），IG）或伊曲替尼（25 mg.kg（-1）.d（-1），IG）或阿卡拉布替尼（25 mg.kg（-1）.d（-1），IG），持续15天。我们发现，口服SOMCL-17-016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，它显示出比伊鲁替尼和阿克拉布替尼更高的体内疗效。我们发现，SOMCL-17-016给药剂量依赖性地抑制CIA小鼠B细胞的抗IgM诱导的增殖和活化，并显著降低RA患者记忆B细胞中抗IgM/抗CD 40刺激的RANKL表达。在RANKL/M-CSF刺激的RAW 264.7细胞中，SOMCL-17-016阻止破骨细胞分化并消除RANK-BTK-PLC γ 2-NFATc 1信号传导。总之，本研究表明，SOMCL-17-016在CIA模型中表现出显著的治疗效果。SOMCL-17-016对B细胞功能和破骨细胞生成具有双重抑制作用，提示其是治疗RA的有希望的候选药物。
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 (Fc gamma R) 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(-1).d(-1), ig), or ibrutinib (25 mg.kg(-1).d(-1), ig) or acalabrutinib (25 mg.kg(-1).d(-1), 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-PLC gamma 2-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.