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Thromb Haemost
DOI: 10.1055/a-2706-9879
Cellular Haemostasis and Platelets

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

Authors

  • Jiayi Chen‡   ‡

    1   Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

  • Shuang Liu‡   ‡

    1   Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

  • Yan Shen‡   ‡

    2   Research Center for Experimental Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

  • Huan Xiong‡   ‡

    3   Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong, China

  • Chao Chen

    4   State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

  • Bing Xiao

    5   Institute for Development and Regenerative Cardiovascular Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

  • Yun Wang

    6   National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China

  • Lu Jin

    3   Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong, China

  • Wanlin Yu

    7   School of Pharmaceutical Sciences, Southern Medical University, Guangdong, China

  • Dounan Xu

    3   Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong, China

  • Zheng Ruan

    1   Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

  • Jingqiu Liu

    4   State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

  • Yaxi Yang

    4   State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

  • Lianghe Mei

    8   Suzhou Institute of Materia Medica, Suzhou, Jiangsu, China

  • Li Hua

    9   School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China

  • Cheng Luo

    3   Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong, China
    4   State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

  • Bing Zhou

    4   State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

  • Kankan Wang

    1   Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

  • Xiaodong Xi   ‡‡

    1   Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

  • Jianhua Mao    ‡‡

    1   Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Funding Information This study was supported by research funding from the National Natural Science Foundation of China (82370134 and 81970112 to X.X., 82350710226 and 82370178 to K.W., and 82304301 to H.X.), Science and Technology Commission of Shanghai Municipality (23S11900400 and 23ZR1439900 to J.M.), and National Key R&D Program of China (2023YFA1800401 to K.W.).
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Abstract

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 β3 mediates outside-in signaling, which is critical for thrombosis, while inside-out signaling maintains hemostasis. Targeting the β3/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 β3/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 β3/Src interaction. In vitro and in vivo studies demonstrated that C109 and C116 effectively suppress thrombosis at levels comparable to high doses of the αIIbβ3 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.

Keywords

antiplatelet agent - hemorrhage - thrombosis - venous thrombosis

‡ These authors contributed equally to this article.


‡‡ These authors share co-corresponding authorship.


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Publikationsverlauf

Eingereicht: 06. April 2025

Angenommen: 18. September 2025

Artikel online veröffentlicht:
10. Oktober 2025

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