Li Wenjie, Mei Wenyi, Jiang Hewei, Wang Jie, Li Xiaoli, Quan Lina, Diao Yanyan, Ma Yanni, Fan Sisi, Xie Zhuwei, Gong Mengdie, Zhu Huan, Bi Dewen, Zhang Feng, Ma Lei, Zhang Jian, Gao Yufeng, Paschalidis Aris, Lin Honghuang, Liu Fangfang, Liu Kangdong, Ye Mingliang, Zhao Zhenjiang, Duan Yajun, Chen Zhuo, Xu Yufang, Xiao Weilie, Tao Shengce, Zhu Lili, Li Honglin
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai, 200237, China.
Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240, China.
Sci China Life Sci. 2025 Jan;68(1):189-203. doi: 10.1007/s11427-024-2706-2. Epub 2024 Aug 29.
Targeting the PD-1/PD-L1 axis with small-molecular inhibitors is a promising approach for immunotherapy. Here, we identify a natural pentacyclic triterpenoid, Pygenic Acid A (PA), as a PD-1 signaling inhibitor. PA exerts anti-tumor activity in hPD-1 knock-in C57BL/6 mice and enhances effector functions of T cells to promote immune responses by disrupting the PD-1 signaling transduction. Furthermore, we identify SHP-2 as the direct molecular target of PA for inhibiting the PD-1 signaling transduction. Subsequently, mechanistic studies suggest that PA binds to a new druggable site in the phosphorylated PD-1 ITSM recognition site of SHP-2, inhibiting the recruitment of SHP-2 by PD-1. Taken together, our findings demonstrate that PA has a potential application in cancer immunotherapy and occupying the phosphorylated ITSM recognition site of SHP-2 may serve as an alternative strategy to develop PD-1 signaling inhibitors. In addition, our success in target recognition provides a paradigm of target identification and confirmation for natural products.
用小分子抑制剂靶向PD-1/PD-L1轴是一种很有前景的免疫治疗方法。在此，我们鉴定出一种天然五环三萜类化合物，致热酸A（PA），作为一种PD-1信号抑制剂。PA在人源化PD-1基因敲入的C57BL/6小鼠中发挥抗肿瘤活性，并通过破坏PD-1信号转导增强T细胞的效应功能以促进免疫反应。此外，我们鉴定出SHP-2是PA抑制PD-1信号转导的直接分子靶点。随后，机制研究表明，PA与SHP-2磷酸化的PD-1 ITSM识别位点中的一个新的可成药位点结合，抑制PD-1对SHP-2的招募。综上所述，我们的研究结果表明，PA在癌症免疫治疗中具有潜在应用价值，占据SHP-2的磷酸化ITSM识别位点可能是开发PD-1信号抑制剂的一种替代策略。此外，我们在靶点识别方面的成功为天然产物的靶点鉴定和确认提供了一个范例。
