Phosphoinositide 3-kinases generate lipid-based second messengers that control an array of intracellular signaling pathways. In particular, phosphoinositide 3-kinases delta (PI3Kδ) is expressed primarily in hematopoietic cells and plays an important role in B-cell development and function. B cells play a critical role in autoimmune diseases by producing autoantibodies. Studies have therefore increasingly focused on PI3Kδ as a therapeutic target for the treatment of inflammatory and autoimmune diseases. One such autoimmune disease is systemic lupus erythematosus (SLE). SLE is a chronic systemic autoimmune disease with repeated recurrence and remission, and autoantibodies play an important role in its pathogenesis. Here, we examined the pharmacological profile of the novel PI3Kδ selective inhibitor AS2819899 and investigated its therapeutic potential against SLE in a NZB/W F1 mouse lupus-like nephritis model, a widely-used SLE mouse model. AS2819899 prevented B and T cell activation in vitro, and inhibited antibody production in a T-cell independent de novo antibody production mouse model. In the spontaneous NZB/W F1 mouse model, AS2819899 treatment significantly reduced anti-dsDNA antibody titers and improved kidney dysfunction. Further, AS2819899 inhibited the memory recall reaction in a T-cell dependent antibody production mouse model, suggesting that AS2819899 can potentially maintain remission of SLE. Moreover, we identified a pharmacodynamics marker for AS2819899 that may be useful in clinical studies. These results indicate that AS2819899 may be an attractive therapeutic candidate for SLE, including the maintenance of remission.

磷酸肌醇3-激酶产生基于脂质的第二信使，其控制一系列细胞内信号传导途径。特别地，磷酸肌醇3-激酶δ（PI3Kδ）主要在造血细胞中表达，并且在B细胞发育和功能中起重要作用。B细胞通过产生自身抗体在自身免疫性疾病中发挥关键作用。因此，研究越来越集中在PI3Kδ作为炎症和自身免疫性疾病的治疗靶标上。一种这样的自身免疫疾病是系统性红斑狼疮（SLE）。SLE是一种慢性全身性自身免疫性疾病，具有反复复发和缓解的症状，自身抗体在其发病机理中起着重要作用。这里，我们研究了新型PI3Kδ选择性抑制剂AS2819899的药理作用，并在NZB / W F1小鼠狼疮样肾炎模型（一种广泛使用的SLE小鼠模型）中研究了其对SLE的治疗潜力。AS2819899在体外阻止B和T细胞活化，并在独立于T细胞的新抗体产生小鼠模型中抑制抗体产生。在自发的NZB / W F1小鼠模型中，AS2819899处理显着降低了抗dsDNA抗体的滴度并改善了肾脏功能障碍。此外，AS2819899在T细胞依赖性抗体产生小鼠模型中抑制了记忆回忆反应，表明AS2819899可以潜在地维持SLE的缓解。此外，我们确定了AS2819899的药效学标志物，可能在临床研究中有用。