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| Discovery of 3‑(Fluoro-imidazolyl)pyridazine Derivatives as Potent STING Agonists with Antitumor Activity | |
| 2025-05-09 | |
| 发表期刊 | JOURNAL OF MEDICINAL CHEMISTRY (IF:6.8[JCR-2023],7.1[5-Year]) |
| ISSN | 0022-2623 |
| EISSN | 1520-4804 |
| 卷号 | 68期号:10页码:9864-9885 |
| 发表状态 | 已发表 |
| DOI | 10.1021/acs.jmedchem.4c01873 |
| 摘要 | Stimulator of interferon genes (STING) represents a promising therapeutic target for cancer and infectious diseases due to its ability to activate innate immune responses. Herein, we describe the discovery of 3-(fluoro-imidazolyl) pyridazine derivatives as potent STING agonists. Our comprehensive investigation, including structural and functional analysis as well as molecular dynamics simulation, suggests that appropriate spatial dimensions may play a crucial role in determining agonist efficacy. Notably, our representative STING agonist A4 demonstrates remarkable binding affinities to various hSTING variants and mSTING, effectively activating STING in both human THP1 and mouse RAW 264.7 cells with EC50 values of 0.06 and 14.15 mu M, respectively. Furthermore, Compound A4 exhibits an excellent pharmacokinetic profile in C57BL/6 mice, and its systemic administration led to significant tumor regression in the B16.F10 tumor-bearing mice, surpassing the efficacy of SR-717. These findings position A4 as a highly promising STING agonist warranting further advanced preclinical development for tumor immunotherapy. |
| URL | 查看原文 |
| 收录类别 | SCI |
| 语种 | 英语 |
| 资助项目 | National Natural Science Foundation of China["T2225002","82273855","81903639"] ; National Key Research and Development Program of China["2023YFC2305904","2022YFC3400504"] ; Youth Innovation Promotion Association CAS[2023296] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB0850000] ; SIMM-SHUTCM Traditional Chinese Medicine Innovation Joint Research Program[E2G805H] ; Open fund of state key laboratory of Pharmaceutical Biotechnology, Nanjing University, China[KF-202301] ; Natural Science Foundation of Shanghai[22ZR1474300] ; Young Elite Scientists Sponsorship Program by CAST[2023QNRC001] ; Postdoctoral Fellowship Program of CPSF[GZC20232846] |
| WOS研究方向 | Pharmacology & Pharmacy |
| WOS类目 | Chemistry, Medicinal |
| WOS记录号 | WOS:001485237300001 |
| 出版者 | AMER CHEMICAL SOC |
| 文献类型 | 期刊论文 |
| 条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/527175 |
| 专题 | 物质科学与技术学院_博士生 物质科学与技术学院 |
| 共同第一作者 | Zhou, Jingyi; Sui, Qibang |
| 通讯作者 | Teng, Dan; Zheng, Mingyue; Zhang, Sulin |
| 作者单位 | 1.Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China 2.University of Chinese Academy of Sciences, Beijing 100049, China 3.School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China 4.School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China 5.Lingang Laboratory, Shanghai 200031, China 6.School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China |
| 通讯作者单位 | 物质科学与技术学院 |
| 推荐引用方式 GB/T 7714 | Hou, Hui,Zhou, Jingyi,Sui, Qibang,et al. Discovery of 3‑(Fluoro-imidazolyl)pyridazine Derivatives as Potent STING Agonists with Antitumor Activity[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(10):9864-9885. |
| APA | Hou, Hui.,Zhou, Jingyi.,Sui, Qibang.,Zhang, Changfa.,Su, Zhaoming.,...&Zhang, Sulin.(2025).Discovery of 3‑(Fluoro-imidazolyl)pyridazine Derivatives as Potent STING Agonists with Antitumor Activity.JOURNAL OF MEDICINAL CHEMISTRY,68(10),9864-9885. |
| MLA | Hou, Hui,et al."Discovery of 3‑(Fluoro-imidazolyl)pyridazine Derivatives as Potent STING Agonists with Antitumor Activity".JOURNAL OF MEDICINAL CHEMISTRY 68.10(2025):9864-9885. |
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