Orthosteric STING inhibition elucidates molecular correction of SAVI STING

Tao Xie (), Max Ruzanov, David Critton, Leidy Merselis, Joseph Naglich, John S. Sack, Ping Zhang, Chunshan Xie, Jeffrey Tredup, Laurel B. Stine, Cameron Messier, David L. Hope, Janet Caceres-Cortes, Luciano Mueller, Alaric J. Dyckman, John A. Newitt, Asmita Choudhury and Stephen C. Wilson ()
Additional contact information
Tao Xie: Bristol Myers Squibb
Max Ruzanov: Bristol Myers Squibb
David Critton: Bristol Myers Squibb
Leidy Merselis: 250 Water St
Joseph Naglich: Bristol Myers Squibb
John S. Sack: Bristol Myers Squibb
Ping Zhang: Bristol Myers Squibb
Chunshan Xie: Bristol Myers Squibb
Jeffrey Tredup: Bristol Myers Squibb
Laurel B. Stine: 250 Water St
Cameron Messier: 250 Water St
David L. Hope: 250 Water St
Janet Caceres-Cortes: Bristol Myers Squibb
Luciano Mueller: Bristol Myers Squibb
Alaric J. Dyckman: Bristol Myers Squibb
John A. Newitt: Bristol Myers Squibb
Asmita Choudhury: Jigani Link Road
Stephen C. Wilson: 250 Water St

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract While the progression of STING activators into the clinic has been successful, the discovery and clinical progression of STING inhibitors remain elusive. Questions persist about the molecular properties needed to distinguish between a STING activator and inhibitor, particularly within SAVI disease, a monogenic autoinflammatory disease that renders STING constitutively active, and how different conformations correlate to function. In this work, we use an orthosteric STING activator and inhibitor from the same chemical series to discover that STING M271 is a critical residue for molecular activation that can be leveraged as a unique molecular signature for pharmacological or genetically driven activation and inhibition. Furthermore, we demonstrate how the therapeutic requirements of a molecular corrector of SAVI STING differs from an orthosteric STING inhibitor, and why this is important for the SAVI disease population.

Date: 2025
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DOI: 10.1038/s41467-025-60632-5

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