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

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

  • J Med Chem. 2025 May 22;68(10):9864-9885. doi: 10.1021/acs.jmedchem.4c01873.
Hui Hou 1 2,  Jingyi Zhou 3 4,  Qibang Sui 1 2,  Changfa Zhang 5,  Zhaoming Su 5,  Rongrong Cui 1 2,  Bin Shan 1,  Peijia Xu 1 5,  Zhengyang Chen 1 2,  Bing Jiang 5,  Manjia Li 5,  Keke Zhang 1 5,  Yajie Wang 1 2 6,  Ning Ma 1 2 6,  Dan Teng 1 2,  Mingyue Zheng 1 2 3 4 6,  Sulin Zhang 1 2
Affiliations

Affiliations

  • 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 Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 4 Lingang Laboratory, Shanghai 200031, China.
  • 5 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 6 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
PMID: 40344198 DOI: 10.1021/acs.jmedchem.4c01873
Abstract

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 μM, 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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