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Potent Inhibition of Arterial Thrombosis and Venous Thrombogenesis Subject to Adequate Hemostasis via Disrupting β3/Src Interaction in Platelets

文献类型：期刊论文

作者Chen, Jiayi4; Liu, Shuang4; Shen, Yan3; Xiong, Huan2; Chen, Chao; Xiao, Bing9; Wang, Yun8; Jin, Lu2; Yu, Wanlin7; Xu, Dounan
刊名THROMBOSIS AND HAEMOSTASIS
出版日期2025-10-10
页码18
关键词antiplatelet agent hemorrhage thrombosis venous thrombosis
ISSN号0340-6245
DOI10.1055/a-2706-9879
英文摘要Background Antiplatelet and anticoagulation are the cornerstones for arterial and venous thrombosis, respectively; however, hemorrhage remains a significant clinical challenge. Platelets are crucial for arterial thrombosis and contribute to venous thrombosis. Integrin beta 3 mediates outside-in signaling, which is critical for thrombosis, while inside-out signaling maintains hemostasis. Targeting the beta 3/Src interactions to selectively inhibit outside-in signaling offers a promising antithrombotic strategy without compromising hemostasis. Objectives To develop more potent small molecules that selectively disrupt the beta 3/Src interaction, thereby inhibiting arterial and venous thrombogenesis without increasing bleeding risk. Methods Building on the previously identified compound DCDBS84, we developed the structurally modified small molecules C109 and C116, with enhanced affinity for the Src SH3 domain. Their antithrombotic effects on both arterial and venous thrombosis were systematically evaluated through in vitro and in vivo studies. The impact on hemostatic function was assessed using a tail-bleeding model. Additionally, the drug developability of C109 was assessed via pharmacokinetic (PK) and metabolite analysis. Results C109 and C116 exhibited superior efficacy in disrupting the beta 3/Src interaction. In vitro and in vivo studies demonstrated that C109 and C116 effectively suppress thrombosis at levels comparable to high doses of the alpha IIb beta 3 antagonist integrilin, without elevating bleeding risk. In the Stenosis Model, C109 and C116 significantly reduced venous thrombogenesis by suppressing platelet activation and neutrophil extracellular trap formation. Additionally, C109 displayed favorable PK properties and robust metabolic stability. Conclusion These findings identify promising small molecules that inhibit thrombosis while maintaining hemostasis, providing new avenues for safer and more effective clinical management.
WOS关键词DUAL ANTIPLATELET THERAPY ; ASPIRIN ; DISEASE ; ACTIVATION ; ASSOCIATION ; RIVAROXABAN ; GUIDELINE ; UPDATE ; RISK
资助项目National Natural Science Foundation of China
WOS研究方向Hematology ; Cardiovascular System & Cardiology
语种英语
WOS记录号WOS:001591721200001
出版者GEORG THIEME VERLAG KG
源URL[http://119.78.100.183/handle/2S10ELR8/321660]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Mao, Jianhua
作者单位1.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Zhongshan Inst Drug Discovery, Zhongshan, Guangdong, Peoples R China
3.Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Res Ctr Expt Med, Shanghai, Peoples R China
4.Shanghai Jiao Tong Univ, Natl Res Ctr Translat Med Shanghai, State Key Lab Med Genom,Ruijin Hosp,Sch Med, Shanghai Inst Hematol,Collaborat Innovat Ctr Hema, Shanghai 200025, Shanghai, Peoples R China
5.Suzhou Inst Chinese Mat Med, Suzhou, Jiangsu, Peoples R China
6.Shanghai Jiao Tong Univ, Sch Med, Sch Publ Hlth, Shanghai, Peoples R China
7.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou, Guangdong, Peoples R China
8.Soochow Univ, Jiangsu Inst Hematol, Natl Clin Res Ctr Hematol Dis, Affiliated Hosp 1, Suzhou, Peoples R China
9.Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Inst Dev & Regenerat Cardiovasc Med, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Jiayi,Liu, Shuang,Shen, Yan,et al. Potent Inhibition of Arterial Thrombosis and Venous Thrombogenesis Subject to Adequate Hemostasis via Disrupting β3/Src Interaction in Platelets[J]. THROMBOSIS AND HAEMOSTASIS,2025:18.
APA Chen, Jiayi.,Liu, Shuang.,Shen, Yan.,Xiong, Huan.,Chen, Chao.,...&Mao, Jianhua.(2025).Potent Inhibition of Arterial Thrombosis and Venous Thrombogenesis Subject to Adequate Hemostasis via Disrupting β3/Src Interaction in Platelets.THROMBOSIS AND HAEMOSTASIS,18.
MLA Chen, Jiayi,et al."Potent Inhibition of Arterial Thrombosis and Venous Thrombogenesis Subject to Adequate Hemostasis via Disrupting β3/Src Interaction in Platelets".THROMBOSIS AND HAEMOSTASIS (2025):18.

入库方式： OAI收割

来源：上海药物研究所

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