Discovery of an Orally Bioavailable STING Inhibitor with In Vivo Anti-Inflammatory Activity in Mice with STING-Mediated Inflammation

The cyclic GMP-AMP synthase (cGAS)-stimulator of the interferon genes (STING) pathway plays a key role in triggering interferon and inflammatory responses against microbial invasion or tumor. However, aberrant activation of the cGAS-STING pathway is associated with a variety of inflammatory and autoimmune diseases, and thus inhibition of STING is regarded as a potential new approach to treating these diseases. Herein, we report a series of novel indolyl-urea derivatives as STING inhibitors. The representative compound 42 exhibited potent STING inhibitory activity, acceptable pharmacokinetic properties, and good in vivo safety profiles. Mechanistically, 42 could block the palmitoylation of the STING protein and STING downstream signaling. Importantly, oral administration of 42 could effectively suppress STING-mediated inflammation in 10-carboxymethyl-9-acridanone (CMA)-treated mouse and Trex1^-/- mouse. Together, compound 42 represents a promising STING inhibitor for treating STING-associated inflammatory and autoimmune diseases.