Preclinical Pharmacology Characterization of Sovleplenib (HMPL-523), an Orally Available Syk Inhibitor

被引：6

作者：

Cai, Yu ^{[1
]}

He, Jianlin ^{[1
]}

Wu, Zhipeng ^{[1
]}

He, Weigang ^{[1
]}

Dai, Xiaoming ^{[1
]}

Xu, Yan ^{[1
]}

Cheng, Min ^{[1
]}

Yang, Na ^{[1
]}

Ren, Yongxin ^{[1
]}

Wang, Guanglin ^{[1
]}

Wang, Jian ^{[1
]}

Sai, Yang ^{[1
]}

Jia, Hong ^{[1
]}

Dai, Guangxiu ^{[1
]}

Li, Xiong ^{[1
]}

Su, Weiguo ^{[1
]}

机构：

[1] HUTCHMED Ltd, Bldg 4,720 Cailun Rd Zhangjiang Hitech Pk,Pudong, Shanghai 201203, Peoples R China

来源：

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | 2024年 / 388卷 / 01期

关键词：

TYROSINE KINASE; RHEUMATOID-ARTHRITIS; R406;

D O I：

10.1124/jpet.123.001752

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Spleen tyrosine kinase (Syk) is an intracellular tyrosine kinase in-volved in the signal transduction in immune cells mainly. Its aber-rant regulation is associated with diversified allergic disorders, autoimmune diseases and B cell malignancies. Therefore, inhibi-tion of Syk is considered a reasonable approach to treat autoim-mune/inflammatory diseases and B cell malignancies. Here we described the preclinical characterization of sovleplenib, 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 im-mune 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).

引用

页码：156 / 170

页数：15

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