Discovery of a New Tetrahydroquinoline-Based Chemotype for STING Inhibition with In Vivo Efficacy against Acute...

Aberrant activation of the stimulator of interferon genes (STING) drives excessive type I interferon and inflammatory responses implicated in autoimmune and inflammatory diseases, including acute kidney injury (AKI). Here, we report the discovery of a tetrahydroquinoline-based STING inhibitor chemotype, represented by KSI-028, that expands the limited scaffold diversity of current small-molecule STING inhibitors. Mechanistic studies suggest that KSI-028 engages STING through a noncanonical, likely allosteric, binding mode with sustained target engagement. KSI-028 potently suppressed STING-dependent signaling and reduced type I interferon and pro-inflammatory cytokine production in both murine and human cells. In a cisplatin-induced AKI mouse model, KSI-028 attenuated renal and hepatic injury and down-regulated STING-associated inflammatory gene expression. These findings establish the tetrahydroquinoline scaffold as a promising foundation for the development of next-generation STING inhibitors with alternative target engagement modes for the treatment of STING-driven inflammatory disorders.