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Discovery of 3-(Fluoro-imidazolyl)pyridazine Derivatives as Potent STING Agonists with Antitumor Activity

文献类型：期刊论文

作者Hou, Hui5,6; Zhou, Jingyi2,3; Sui, Qibang5,6; Zhang, Changfa4; Su, Zhaoming4; Cui, Rongrong5,6; Shan, Bin6; Xu, Peijia4,6; Chen, Zhengyang5,6; Jiang, Bing4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-05-09
卷号68期号:10页码:9864-9885
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c01873
英文摘要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.
WOS关键词CYCLIC GMP-AMP ; ACTIVATION ; PARAMETERS ; STIMULATOR ; PROTEIN ; ADAPTER ; LIGAND ; MOUSE
资助项目National Natural Science Foundation of China[T2225002] ; National Natural Science Foundation of China[82273855] ; National Natural Science Foundation of China[81903639] ; National Key Research and Development Program of China[2023YFC2305904] ; National Key Research and Development Program of China[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
语种英语
WOS记录号WOS:001485237300001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/317866]  
专题新药研究国家重点实验室
通讯作者Teng, Dan; Zheng, Mingyue; Zhang, Sulin
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Lingang Lab, Shanghai 200031, Peoples R China
3.Shanghai Tech Univ, Sch Phys Sci & Technol, Shanghai 201210, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China
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.

入库方式： OAI收割

来源：上海药物研究所

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