脾酪氨酸激酶（Syk）是一种细胞内酪氨酸激酶，主要参与免疫细胞的信号转导。其异常调节与多种过敏性疾病、自身免疫性疾病和 B 细胞恶性肿瘤有关。因此，抑制Syk被认为是治疗自身免疫/炎症性疾病和B细胞恶性肿瘤的合理方法。在这里，我们描述了 sovleplenib (HMPL-523) 在几种啮齿动物自身免疫性疾病模型中的临床前表征，sovleplenib 是一种新型、高效、选择性的口服 Syk 抑制剂。在重组酶测定中，Sovleplenib 有效抑制 Syk 活性，并在体外抑制各种免疫细胞系和人全血中的 Syk 依赖性细胞功能。此外，口服 sovleplenib 在免疫性血小板减少症 (ITP)、自身免疫性溶血性贫血 (AIHA) 和慢性移植物抗宿主病 (cGVHD) 小鼠模型以及胶原诱导关节炎大鼠模型中表现出强大的体内疗效（CIA）分别以剂量依赖性方式。总的来说，这些结果明确支持 sovleplenib 作为治疗自身免疫性疾病的治疗剂。 Sovleplenib 正在全球范围内开发用于 ITP（III 期，NCT05029635，Ib/II 期，NCT03951623）、wAIHA（II/III 期，NCT05535933）和 B 细胞淋巴瘤（I 期，NCT02857998，NCT03779113）。意义说明 Syk 是多种对免疫功能很重要的受体下游信号通路的关键介质，包括 B 细胞受体、带有 Fc 受体 (FcR) 的免疫球蛋白受体。 Syk 的抑制可以为自身免疫性疾病和血液恶性肿瘤提供一种新的治疗方法。该手稿描述了 sovleplenib（一种新型 Syk 抑制剂）在体外酶和细胞测定以及体内几种小鼠自身免疫性疾病模型中的临床前药理学特征。版权所有 © 2023 美国药理学和实验治疗学会。

Spleen tyrosine kinase (Syk) is an intracellular tyrosine kinase involved in the signal transduction in immune cells mainly. Its aberrant regulation is associated with diversified allergic disorders, autoimmune diseases and B cell malignancies. Therefore, inhibition of Syk is considered a reasonable approach to treat autoimmune/inflammatory diseases and B cell malignancies. Here we described the preclinical characterization of sovleplenib (HMPL-523), a novel, highly potent and selective, oral Syk inhibitor, in several rodent autoimmune disease models. Sovleplenib potently inhibited Syk activity in a recombinant enzymatic assay and Syk-dependent cellular functions in various immune cell lines and human whole blood in vitro. Furthermore, sovleplenib, by oral administration, demonstrated strong in vivo efficacies in murine models of immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and chronic graft-versus-host disease (cGVHD), and a rat model of collagen induced arthritis (CIA) respectively, in a dose-dependent manner. Collectively, these results clearly supported sovleplenib as a therapeutic agent in the treatment of autoimmune diseases. Sovleplenib is being globally developed for ITP (Phase III, NCT05029635, Phase Ib/II, NCT03951623), wAIHA (Phase II/III, NCT05535933) and B-cell lymphoma (Phase I, NCT02857998, NCT03779113). Significance Statement Syk is a key mediator of signaling pathways downstream of a wide array of receptors important for immune functions, including the B cell receptor, immunoglobulin receptors bearing Fc receptors (FcRs). Inhibition of Syk could provide a novel therapeutic approach for autoimmune diseases and hematologic malignancies. The manuscript describes the preclinical pharmacology characterization of sovleplenib, a novel Syk inhibitor, in enzymatic and cellular assays in vitro and several murine autoimmune disease models in vivo.Copyright © 2023 American Society for Pharmacology and Experimental Therapeutics.