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Design, synthesis and structure-activity relationship studies of novel macrocyclic 2,4-diaminopyrimidines as HPK1 inhibitors

文献类型：期刊论文

作者Wu, Feifei1,9; Sun, Jiaqi1,8; Xu, Mingyang7; Li, Huiyu1,8; Wei, Jiarui6; Zhang, Shunlai5; An, Qi7; Sun, Yaoliang9; Xu, Lei4; Li, Jia1,2,3,4,7
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2025-10-01
卷号128页码:12
关键词Macrocycle Kinase Inhibitors HPK1 Cancer immunotherapy
ISSN号0968-0896
DOI10.1016/j.bmc.2025.118265
通讯作者Meng, Linghua(lhmeng@simm.ac.cn) ; Xu, Shilin(slxu@simm.ac.cn)
英文摘要Hematopoietic progenitor kinase 1 (HPK1) functions as a key negative regulator of T cell receptor signaling and has been considered a potential target for cancer immunotherapy. Despite great progress in developing HPK1 inhibitors, no small-molecule inhibitors have been approved for cancer treatment to date. Herein, we describe the design and synthesis of a novel series of macrocyclic 2,4-diaminopyrimidine derivatives as HPK1 inhibitors. Among these, the representative compound 21 exhibited potent HPK1 inhibition with an IC50 value of 1.0 nM in an ADP-Glo assay. Furthermore, compound 21 effectively inhibited phosphorylation of the downstream adaptor protein SLP76 and enhanced IL-2 secretion in human Jurkat T cells. Taken together, this study further validates macrocyclization as an effective strategy for designing HPK1 inhibitors with innovative scaffolds and offers compound 21 as a structurally novel lead compound for the development of HPK1 inhibitors.
WOS关键词HEMATOPOIETIC PROGENITOR KINASE ; ACQUIRED-RESISTANCE ; CELL ; IMMUNOTHERAPY ; DISCOVERY
资助项目National Natural Science Foundation of China[22277128] ; National Natural Science Foundation of China[22307132] ; Science and Technology Commission of Shanghai Municipality[22ZR1474400] ; Shanghai Sailing Program[22YF1457500] ; National Key Research and Development Program of China[2023YFA1800804]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:001509109800001
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/318410]  
专题中国科学院上海药物研究所
通讯作者Meng, Linghua; Xu, Shilin
作者单位1.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 110039, Peoples R China
2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Stake Key Lab Chem Biol, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
5.Zunyi Med Univ, Zhuhai Campus, Zhuhai, Peoples R China
6.Lanzhou Univ, Sch Life Sci, Lanzhou 730000, Peoples R China
7.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
8.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
9.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Wu, Feifei,Sun, Jiaqi,Xu, Mingyang,et al. Design, synthesis and structure-activity relationship studies of novel macrocyclic 2,4-diaminopyrimidines as HPK1 inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2025,128:12.
APA Wu, Feifei.,Sun, Jiaqi.,Xu, Mingyang.,Li, Huiyu.,Wei, Jiarui.,...&Xu, Shilin.(2025).Design, synthesis and structure-activity relationship studies of novel macrocyclic 2,4-diaminopyrimidines as HPK1 inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY,128,12.
MLA Wu, Feifei,et al."Design, synthesis and structure-activity relationship studies of novel macrocyclic 2,4-diaminopyrimidines as HPK1 inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY 128(2025):12.

入库方式： OAI收割

来源：上海药物研究所

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