The Development of UM-203, A Reversible Covalent STING Antagonist.
Leonard Barasa, Leo DeOrsey, Maeve D O'Reilly, Shruti Choudhary, Sara E Cahill, Anukriti Mathur, Akumalla Allabaji, Srinivasa Rao Vidadala, Sujit Kumar Sarkar, Santoshkumar N Patil, Harikesh Kalonia, Jeffrey Hale, Fiachra Humphries, Katherine A Fitzgerald, Paul R Thompson
Abstract
Open AccessThe cGAS-STING pathway is a critical component of the innate immune system, responsible for detecting cytosolic DNA and triggering inflammatory signaling. While essential for host defense, aberrant activation of this pathway is linked to a range of inflammatory and autoimmune disorders. Consequently, STING has emerged as a compelling therapeutic target. Herein we report the development of the first reversible covalent STING inhibitor, i.e., UM-203 which employs an alkyne-thiazole warhead. UM-203 inhibits STING-dependent signaling in both mouse and human systems. Notably, UM-203 maintains activity against the most prevalent human STING variant (R232), effectively suppresses STING signaling in primary human CD14+ monocytes, and exhibits moderate metabolic stability. Collectively, these findings highlight UM-203 as a promising scaffold for the development of therapeutics targeting STING-driven inflammatory and autoimmune diseases.