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Development of a series of quinazoline-2,5-diamine derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors

文献类型：期刊论文

作者Shi, Huanyu1,2; Tang, Haotian1,3; Li, Yan3; Chen, Danqi2; Liu, Tongchao2; Chen, Yuting1,2; Wang, Xin2; Chen, Lin2; Wang, Ying2; Xie, Hua1,3,4
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-02-15
卷号248页码:20
ISSN号0223-5234
关键词Cancer immunotherapy SAR study HPK1 inhibitors Quinazoline-2 5-diamine IL-2 production
DOI10.1016/j.ejmech.2022.115064
通讯作者Xie, Hua(hxie@simm.ac.cn) ; Xiong, Bing(bxiong@simm.ac.cn)
英文摘要Hematopoietic progenitor kinase 1 (HPK1) is a serine/threonine kinase that serves as the negative regulator of multiple immune signaling pathways. Genetic studies using HPK1 knockout and kinase-dead mice suggested that inhibiting HPK1 either alone or in combination with immune checkpoint blockade could be a promising strategy in cancer immunotherapy. Herein, we report the design, synthesis and structure-activity relationship (SAR) study of a series of potent HPK1 inhibitors bearing quinazoline-2,5-diamine scaffold. Three rounds of SAR exploration led to the identification of 9h, the most potent compound in this series which harbors a 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl substituent. Further biological assessments using human immune cells demonstrated that 9h could strongly inhibit downstream phosphorylation, augment interleukin-2 (IL-2) pro-duction and reverse prostaglandin E2 (PGE2)-induced immune suppression. Overall, our study on these quinazoline-2,5-diamine derivatives provided not only a tool compound for the community to help with eluci-dating the HPK1 pharmacology, but also a reliable reference for subsequent development of HPK1 inhibitors.
WOS关键词SMALL MOLECULES ; OPEN-LABEL ; CELL ; NIVOLUMAB ; OPPORTUNITIES ; CHEMOTHERAPY ; IMMUNITY
资助项目Natural Science Foundation of China[82173658] ; High-level Innovative Research Institute[2021B0909050003]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号WOS:000918137900001
源URL[http://119.78.100.183/handle/2S10ELR8/303687]  
专题中国科学院上海药物研究所
通讯作者Xie, Hua; Xiong, Bing
作者单位1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Zhongshan Inst Drug Discovery, Zhongshan 528400, Peoples R China
推荐引用方式
GB/T 7714		 Shi, Huanyu,Tang, Haotian,Li, Yan,et al. Development of a series of quinazoline-2,5-diamine derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,248:20.
APA Shi, Huanyu.,Tang, Haotian.,Li, Yan.,Chen, Danqi.,Liu, Tongchao.,...&Xiong, Bing.(2023).Development of a series of quinazoline-2,5-diamine derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,248,20.
MLA Shi, Huanyu,et al."Development of a series of quinazoline-2,5-diamine derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 248(2023):20.

入库方式： OAI收割

来源：上海药物研究所

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