Blocking the PD-1 signal transduction by occupying the phosphorylated ITSM recognition site of SHP-2

作     者：Wenjie Li Wenyi Mei Hewei Jiang Jie Wang Xiaoli Li Lina Quan Yanyan Diao Yanni Ma Sisi Fan Zhuwei Xie Mengdie Gong Huan Zhu Dewen Bi Feng Zhang Lei Ma Jian Zhang Yufeng Gao Aris Paschalidis Honghuang Lin Fangfang Liu Kangdong Liu Mingliang Ye Zhenjiang Zhao Yajun Duan Zhuo Chen Yufang Xu Weilie Xiao Shengce Tao Lili Zhu Honglin Li 

作者机构：Innovation Center for AI and Drug DiscoveryEast China Normal University Shanghai Key Laboratory of New Drug DesignSchool of PharmacyEast China University of Science&Technology Shanghai Center for Systems BiomedicineKey Laboratory of Systems Biomedicine (Ministry of Education)Shanghai Jiao Tong University Lingang Laboratory Key Laboratory of Medicinal Chemistry for Natural ResourceMinistry of EducationYunnan Characteristic Plant Extraction LaboratoryYunnan Provincial Center for Research&Development of Natural ProductsState Key Laboratory for Conservation and Utilization of Bio-Resources in YunnanSchool of Pharmacy and School of Chemical Science and TechnologyYunnan University CAS Key Laboratory of Separation Sciences for Analytical ChemistryNational Chromatographic R&A CenterDalian Institute of Chemical PhysicsChinese Academy of Sciences Department of CardiologyThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of China Department of Infectious DiseasesThe First Affiliated Hospital of Anhui Medical University Department of MedicineUniversity of Massachusetts Chan Medical School Department of PathophysiologySchool of Basic Medical SciencesAcademy of Medical ScienceCollege of MedicineZhengzhou University 

出 版 物：《Science China Life Sciences》 (中国科学:生命科学(英文版))

年 卷 期：2024年

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

基　　金：supported in part by the National Natural Science Foundation of China (81825020, 82150208, 82260682) the National Key R&D Program of China (2022YFC3400501, 2022YFC3400504) the Shanghai Science and Technology Commission Biomedical Science and Technology Support Special Project (21S11907900, 20S11901000) Project of Yunnan Characteristic Plant Screening and R&D Service CXO Platform (2022YKZY001) sponsored by the National Program for Special Supports of Eminent Professionals and National Program for Support of Top-notch Young Professionals 

摘      要：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.