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, and Paul R. Thompson
ACS Medicinal Chemistry Letters 2025
DOI: 10.1021/acsmedchemlett.5c00611
The 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.
