Design, synthesis, and activity evaluation of novel STING inhibitors based on C170 and H151

Abstract

Stimulating the STING signaling pathway for immune system activation is considered a promising strategy for cancer treatment. However, activating the STING pathway can lead to adverse effects, as aberrant activation or specific mutations in STING may result in autoimmune and inflammatory diseases. Therefore, the development of STING inhibitors is equally important. In this study, we first introduced hydroxyl groups into the STING inhibitors C170 and H151, creating functional sites for further modification. Then the introduction of various substituents resulted in the identification of more potent inhibitors, Y2 and HY2, which effectively suppressed the activation of the STING pathway in THP1 and RAW264.7 cells. Compounds Y2 and HY2 demonstrated potent anti-inflammatory effects in mice cisplatin-induced acute kidney injury models by inhibiting the STING pathway. Collectively, Y2 and HY2 warrant further investigation as novel anti-inflammatory agents.