Design, Synthesis, and biological evaluation of 7H-Pyrrolo[2,3-d] pyrimidines as potent HPK1 kinase inhibitors
文献类型：期刊论文
| 作者 | Wu, Feifei1,10; Li, Huiyu1,9; Li, Weiqiang1,8; Zhang, Laishun7; An, Qi6; Sun, Jiaqi1,9; Zhang, Qian6; Sun, Yaoliang10; Xu, Lei5; Yu, Jinghua8 |
| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
 |
| 出版日期 | 2025-03-01 |
| 卷号 | 119页码:13 |
| 关键词 | Optimization Hematopoietic progenitor kinase 1 Inhibitor Cancer immunotherapy |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/j.bmc.2025.118079 |
| 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) has emerged as a promising target for cancer immunotherapy due to its critical role as a negative regulator of T cell receptor (TCR) signaling. Despite this potential, no HPK1 inhibitors have been approved for cancer treatment, underscoring the need for structurally novel inhibitors. Herein, we describe the design, synthesis and biological evaluation of a series of potent HPK1 inhibitors based on our previously identified hit 9. Among them, compound 24 demonstrated strong HPK1 inhibition (IC50 of 10.1 nM) and effectively suppressed phosphorylation of the downstream protein SLP76. Notably, compound 24 exhibited enhanced potency in promoting IL-2 secretion in Jurkat T cells, reduced cellular toxicity, and improved liver microsomal stability compared to hit 9. Overall, this study provides a promising lead compound for further optimization as a candidate for cancer immunotherapy. |
| WOS关键词 | DISCOVERY ; ACTIVATION |
| 资助项目 | National Natural Science Foundation of China[82103973] ; Science and Technology Commission of Shanghai Municipality[22ZR1474400] ; State Key Laboratory of Chemical Biology ; Shanghai Sailing Program[22YF1457500] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001421605800001 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316233]  |
| 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, Beijing 100049, Peoples R China 2.Shandong Lab Yantai Drug Discovery, Bohai Rim Adv Res Inst Drug Discovery, Yantai 264117, Shandong, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 5.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Inst Drug Discovery & Dev, Zhongshan 528400, Peoples R China 6.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Dept Angiocarpy, Nanjing 210023, Peoples R China 7.Zunyi Med Univ Zhuhai Campus, Zhuhai, Peoples R China 8.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Metab & Pharmacokinet, Shanghai 201203, Peoples R China 9.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Chem Biol, Shanghai 201203, Peoples R China 10.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,Li, Huiyu,Li, Weiqiang,et al. Design, Synthesis, and biological evaluation of 7H-Pyrrolo[2,3-d] pyrimidines as potent HPK1 kinase inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2025,119:13. |
| APA | Wu, Feifei.,Li, Huiyu.,Li, Weiqiang.,Zhang, Laishun.,An, Qi.,...&Xu, Shilin.(2025).Design, Synthesis, and biological evaluation of 7H-Pyrrolo[2,3-d] pyrimidines as potent HPK1 kinase inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY,119,13. |
| MLA | Wu, Feifei,et al."Design, Synthesis, and biological evaluation of 7H-Pyrrolo[2,3-d] pyrimidines as potent HPK1 kinase inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY 119(2025):13. |
入库方式： OAI收割
来源：上海药物研究所
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