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The Development of UM-232, a Covalent STING Antagonist
Leonard Barasa1,2, Leo DeOrsey1,2, Maeve D O'Reilly1,2
1Program in Chemical Biology, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, United States.
None:
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central regulator of innate immunity, sensing cytosolic DNA and initiating inflammatory signaling. Aberrant activation of this pathway drives autoimmune and inflammatory pathologies, positioning STING as a compelling therapeutic target. Here, we describe the structure-activity relationship (SAR)-guided optimization of LB-246 to yield UM-232, a next-generation STING inhibitor with markedly improved potency and selectivity. Rational design incorporated two key modifications: substitution of the N-α amide with an isosteric triazole and replacement of the C-terminal benzimidazole with a spirocyclic piperidine-oxetane moiety. These changes conferred an 8-fold increase in cellular potency, robust inhibition of STING oligomerization, and enhanced metabolic stability. Incorporation of an α-methyl chloroacetamidine warhead further augmented activity. Collectively, UM-232 establishes a promising chemical scaffold for therapeutic development targeting STING-driven autoimmune and inflammatory disorders.
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