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. <b>BB-Cl-amidine</b> and <b>LB244</b> are recently reported STING antagonists that work by blocking STING oligomerization. Herein, we describe the diverse strategies taken to optimize the potency of <b>LB244</b>. These efforts led to the development of <b>UM-242</b> and <b>UM-259</b>. <b>UM-242</b> and <b>UM-259</b> both inhibit mouse and human STING-dependent signaling with efficacy similar to that of <b>LB244</b>. We further show that <b>UM-242</b> and <b>UM-259</b> maintain their potency against the most common human STING variant (R232) and inhibit STING signaling in primary human CD14+ monocytes. In summary, <b>UM-242</b> and <b>UM-259</b> represent additional novel scaffolds for the development of therapeutics to treat STING-dependent inflammatory diseases.