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Design, Synthesis, and Pharmacological Evaluation of Isoindoline Analogues as New HPK1 Inhibitors

文献类型：期刊论文

作者Xie, Chenghu1,6; Liu, Bo3,5; Song, Zilan1,6; Yang, Ye3,5; Dai, Mengdi3,5; Gao, Yinglei3,5; Yao, Yujia2; Ding, Chunyong1,6; Ai, Jing3,5; Zhang, Ao1,2,4,6
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-11-22
卷号66期号:23页码:16201-16221
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c01571
通讯作者Ai, Jing(jai@simm.ac.cn) ; Zhang, Ao(ao6919zhang@sjtu.edu.cn)
英文摘要Hematopoietic progenitor kinase 1 (HPK1) is an important negative regulator in T-cell receptor signaling and as a promising key target for immunotherapy. Herein, based on the reported HPK1 inhibitor 2 featuring an isofuranone component, a structural optimization approach was conducted leading to several series of derivatives characterized by containing an isoindoline structural motif. Compound 49 was identified as a new potent HPK1 inhibitor with an IC50 value of 0.9 nM, more potent than compound 2 (5.5 nM). It also has an improved IV profile in rats and enhanced aqueous solubility. It effectively inhibited pSLP76 and reinvigorated T-cell receptor (TCR) signaling, promoting T-cell function and cytokine production both in nai''ve and antigen-specific T cells. Furthermore, compound 49 reversed the inhibition on T-cell activity mediated by classic immunosuppressive factors in the tumor microenvironment (TME). In the murine CT-26 tumor model, this compound reinvigorated the T cell and synergistically enhanced the antitumor efficacy of anti-PD1 at a well-tolerant dosage.
WOS关键词PROGENITOR KINASE 1 ; TUMOR
资助项目National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[2021ZD0204004] ; Natural Science Foundation of China for Innovation Research Group[82273767] ; Natural Science Foundation of China for Innovation Research Group[82073073] ; Natural Science Foundation of China for Innovation Research Group[82122045] ; Natural Science Foundation of China for Innovation Research Group[82173834] ; National Natural Science Foundation of China[ZJ2021-ZD-007] ; Major Projects for Shanghai Zhangjiang National Independent Innovation of China[SHSMU-ZDCX20210802] ; Innovative research team of high-level local universities in Shanghai
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:001142976100001
源URL[http://119.78.100.183/handle/2S10ELR8/308666]  
专题新药研究国家重点实验室
通讯作者Ai, Jing; Zhang, Ao
作者单位1.Shanghai Jiao Tong Univ, Shanghai Frontiers Sci Ctr Drug Target Identificat, Sch Pharmaceut Sci, Shanghai 200240, Peoples R China
2.Hangzhou Med Coll, Sch Pharmaceut Sci, Hangzhou 310053, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Lingang Lab, Shanghai 200210, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Shanghai Jiao Tong Univ, Natl Key Lab Innovat Immunotherapy, Shanghai 200240, Peoples R China
推荐引用方式
GB/T 7714		 Xie, Chenghu,Liu, Bo,Song, Zilan,et al. Design, Synthesis, and Pharmacological Evaluation of Isoindoline Analogues as New HPK1 Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023,66(23):16201-16221.
APA Xie, Chenghu.,Liu, Bo.,Song, Zilan.,Yang, Ye.,Dai, Mengdi.,...&Zhang, Ao.(2023).Design, Synthesis, and Pharmacological Evaluation of Isoindoline Analogues as New HPK1 Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,66(23),16201-16221.
MLA Xie, Chenghu,et al."Design, Synthesis, and Pharmacological Evaluation of Isoindoline Analogues as New HPK1 Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 66.23(2023):16201-16221.

入库方式： OAI收割

来源：上海药物研究所

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