Nitrofuran-Based STING Inhibitors

The cGAS-STING pathway plays a central role in the host response to foreign DNA. While cGAS-STING signaling is essential for antiviral immunity, aberrant STING activation is observed in amyotrophic lateral sclerosis (ALS), lupus, and autoinflammatory diseases such as Aicardi-Goutières syndrome (AGS) and STING associated vasculopathy with onset in infancy (SAVI). Thus, STING inhibitors are likely therapeutic agents. BB-Cl-amidine and LB244 are recently reported STING antagonists that work by blocking STING oligomerization. Herein, we describe the diverse strategies taken to optimize the potency of LB244. These efforts led to the development of UM-242 and UM-259. UM-242 and UM-259 both inhibit mouse and human STING-dependent signaling with efficacy similar to that of LB244. We further show that UM-242 and UM-259 maintain their potency against the most common human STING variant (R232) and inhibit STING signaling in primary human CD14+ monocytes. In summary, UM-242 and UM-259 represent additional novel scaffolds for the development of therapeutics to treat STING-dependent inflammatory diseases.