STING antagonists, synthesized via Povarov-Doebner type multicomponent reaction

The cGAS-STING axis plays an important role in protecting higher organisms against invading pathogens or cancer by promoting the production of cytokines and interferons. However, persistent or uncontrolled activation of this pathway could lead to inflamed environments, which is detrimental to the host in the long run. Persistent activation of STING is known to be the cause of STING-associated vasculopathy with onset in infancy (SAVI) and activated STING is believed to play important roles in worsening various diseased states, such as traumatic brain injury, diabetic kidney disease and colitis. Thus, antagonists of STING could play important roles in managing various inflammatory diseases. Herein, we report the discovery of small molecule STING inhibitors, HSD1077 and analogs, which are facilely synthesized via a Povarov-Doebner type three-component reaction involving an amine, ketone, and aldehyde. Structure-activity relationship, SAR, studies indicate that both the 3H-pyrazolo[4,3-f]quinoline and pyrazole moieties in HSD1077 are critical for STING binding. At concentrations as low as 20 nM, HSD1077 suppressed type-1 interferon expression in both murine RAW macrophages and human THP-1 monocytes upon treatment with 100 mu M 2'-3' cGAMP. Compounds containing the 3H-pyrazolo[4,3-f]quinoline moiety have the potential to be translated into anti-inflammatory compounds via STING inhibition.

Automated summary

The cGAS-STING axis is important in protecting higher organisms against pathogens or cancer. However, overactivation of this pathway can lead to inflammation, which is harmful to the host. STING antagonists, such as HSD1077, have been discovered and shown to inhibit STING binding, suppressing interferon expression and potentially managing various inflammatory diseases.