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Discovery of 7H-Pyrrolo[2,3-d]pyrimidine Derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors

文献类型：期刊论文

作者Wu, Feifei1,5; Li, Huiyu2,5; An, Qi3; Sun, Yaoliang1; Yu, Jinghua4; Cao, Wenting1; Sun, Pu2; Diao, Xingxing4; Meng, Linghua2,5; Xu, Shilin1,5
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-06-05
卷号254页码:15
ISSN号0223-5234
关键词Hematopoietic progenitor kinase 1 (HPK1) Cancer immunotherapy Inhibitor T cell
DOI10.1016/j.ejmech.2023.115355
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) is predominantly expressed in hematopoietic cells and is a negative regulator of T cell receptor (TCR) signaling. Recent studies have demonstrated that HPK1 is a promising therapeutic target for cancer immunotherapy. However, despite significant progress in the development of HPK1 inhibitors, none of them has been approved for cancer therapy. Development of HPK1 inhibitors with a structurally distinct scaffold is still needed. Herein, we describe the design and synthesis of a series of HPK1 inhibitors with a 7H-pyrrolo[2,3-d]pyrimidine scaffold, exemplified by 31. Compound 31 showed potent inhibitory activity against HPK1 with an IC50 value of 3.5 nM and favorable selectivity within a panel of kinases. It also potently inhibited the phosphorylation level of SLP76, a substrate of HPK1, and enhanced the IL-2 secretion in Jurkat cells (human T cell leukemia). Our findings provide new clues for further optimization and development to generate HPK1 inhibitors for cancer immunotherapy.
WOS关键词PROTEIN ; CANCER ; SLP-76
资助项目National Natural Science Foundation of China[82103973] ; National Natural Science Foundation of China[22277128] ; National Natural Science Foundation of China[81973345] ; Shanghai Sailing Program[22YF1457500] ; Lingang Laboratory[LG202103-02-03]
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:000982483700001
源URL[http://119.78.100.183/handle/2S10ELR8/306472]  
专题新药研究国家重点实验室
通讯作者Meng, Linghua; Xu, Shilin
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Ctr Drug Metab & Pharmacokinet, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Wu, Feifei,Li, Huiyu,An, Qi,et al. Discovery of 7H-Pyrrolo[2,3-d]pyrimidine Derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,254:15.
APA Wu, Feifei.,Li, Huiyu.,An, Qi.,Sun, Yaoliang.,Yu, Jinghua.,...&Xu, Shilin.(2023).Discovery of 7H-Pyrrolo[2,3-d]pyrimidine Derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,254,15.
MLA Wu, Feifei,et al."Discovery of 7H-Pyrrolo[2,3-d]pyrimidine Derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 254(2023):15.

入库方式： OAI收割

来源：上海药物研究所

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