Citation: Xuyang Ding, Tongtong Geng, Yongxia Li, Pengming Pan, Zhongtang Li, Zhongjun Li, Xiangbao Meng. Discovery a plasiatine-based potent SHP2 activator as a potential anti-atherosclerotic agent[J]. Chinese Chemical Letters, ;2026, 37(10): 112140. doi: 10.1016/j.cclet.2025.112140 shu

Discovery a plasiatine-based potent SHP2 activator as a potential anti-atherosclerotic agent

State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China

zjli@bjmu.edu.cn

xbmeng@bjmu.edu.cn

Received Date: 27 July 2025
Revised Date: 19 November 2025
Accepted Date: 20 November 2025
Available Online: 21 November 2025

Figures(4)

The Src homology 2 domain-containing phosphatase 2 (SHP2) plays a pivotal role in cellular processes and is associated with various diseases. Activation of SHP2 has been shown to be effective in inflammation-related diseases such as colitis, atherosclerosis and Parkinson's disease. Although SHP2 inhibitors have been extensively studied in recent years, especially allosteric inhibitors, only a small number of SHP2 activators exhibiting weak activation effects have been reported. Herein, we developed a facile approach to the total synthesis of plasiatine, which was extracted from the seeds of Plantago asiatica as a direct SHP2 activator. Iterative study on the structure-activity relationship identified a potent SHP2 activator, compound C8, with median effective concentration (EC₅₀) = 0.11 µmol/L and E_max = 3.75-fold. Surface plasmon resonance experiment revealed a robust binding affinity between C8 and the SHP2 catalytic domain, with a dissociation constant (K_d) of 70.4 nmol/L. In vivo study showed that C8 significantly reduced atherosclerotic plaques and increased anti-inflammatory factors, highlighting its potential as an effective anti-atherosclerotic agent.
- SHP2 activator,
- Plasiatine,
- Total synthesis,
- Structure-activity relationship,
- Anti-atherosclerosis
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