Leonard Barasa, Leo DeOrsey, Maeve O’Reilly, Shruti Choudhary, Sara Cahill, Anukriti Mathur, Akumalla Allabaji, Shreekrishna Nellikkalaya, Sourav Paul, Srinivasa Rao Vidadala, Sujit Sarkar, Muruganantham Rajendran, Santoshkumar N. Patil, Harikesh Kalonia, Jeffrey J. Hale, Fiachra Humphries, Katherine A. Fitzgerald, Paul R. Thompson
In response to double stranded DNA (dsDNA), the cGAS-STING pathway activates the innate immune response. While beneficial for detecting invading bacteria and viruses, overactivation of this pathway is associated with the development of several inflammatory and autoimmune diseases, making STING an attractive therapeutic target. Previously, we reported STING inhibitors that employ a nitrofuran warhead; these compounds covalently modify STING and prevent its oligomerization. Herein we describe our efforts to identify alternative electrophilic warheads using UM-001 as a starting scaffold. These efforts led to UM-200, a next-generation inhibitor featuring an alkyne amide warhead. UM-200 potently suppresses STING signaling in murine and human systems, retains activity against the prevalent human STING variant (R232), and effectively inhibits pathway activation in primary human CD14+ monocytes. Notably, UM-200 exhibits markedly improved metabolic stability compared to earlier analogs. These findings position UM-200 as a promising scaffold for developing therapeutics targeting STING-driven inflammatory and autoimmune disorders.