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

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.