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

doi:10.1021/acs.jmedchem.4c01873

	Discovery of 3‑(Fluoro-imidazolyl)pyridazine Derivatives as Potent STING Agonists with Antitumor Activity
	Hou, Hui 1,2; Zhou, Jingyi4,5 ; Sui, Qibang 1,2; Zhang, Changfa 3; Su, Zhaoming 3; Cui, Rongrong 1,2; Shan, Bin 1; Xu, Peijia 1,3; Chen, Zhengyang 1,2; Jiang, Bing 3; Li, Manjia 3; Zhang, Keke 1,3; Wang, Yajie 1,2,6; Ma, Ning 1,2,6; Teng, Dan 1,2; Zheng, Mingyue1,2,4,5,6 ; Zhang, Sulin 1,2
	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.
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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.