2. Academic Validation
  3. Orthosteric STING inhibition elucidates molecular correction of SAVI STING

Orthosteric STING inhibition elucidates molecular correction of SAVI STING

  • Nat Commun. 2025 Jul 1;16(1):5695. doi: 10.1038/s41467-025-60632-5.
Tao Xie 1,  Max Ruzanov 2,  David Critton 2,  Leidy Merselis 3,  Joseph Naglich 4,  John S Sack 2,  Ping Zhang 5,  Chunshan Xie 4,  Jeffrey Tredup 5,  Laurel B Stine 3,  Cameron Messier 3,  David L Hope 3,  Janet Caceres-Cortes 6,  Luciano Mueller 6,  Alaric J Dyckman 7,  John A Newitt 5,  Asmita Choudhury 8,  Stephen C Wilson 9
Affiliations

Affiliations

  • 1 Drug Discovery Analytical, Lead Discovery and Optimization, Discovery & Development Sciences, Bristol Myers Squibb, Lawrenceville, NJ, 08648, USA. tao.xie@bms.com.
  • 2 Structural Biology, Lead Discovery and Optimization, Discovery & Development Sciences, Bristol Myers Squibb, Lawrenceville, NJ, 08648, USA.
  • 3 Discovery Immunology, Bristol Myers Squibb, 250 Water St, Cambridge, MA, 02141, USA.
  • 4 Mechanistic Pharmacology, Discovery & Development Sciences, Bristol Myers Squibb, Lawrenceville, NJ, 08648, USA.
  • 5 Protein Science, Lead Discovery and Optimization, Discovery & Development Sciences, Bristol Myers Squibb, Lawrenceville, NJ, 08648, USA.
  • 6 Drug Discovery Analytical, Lead Discovery and Optimization, Discovery & Development Sciences, Bristol Myers Squibb, Lawrenceville, NJ, 08648, USA.
  • 7 Immunology Chemistry, Discovery & Development Sciences, Bristol Myers Squibb, Lawrenceville, NJ, 08648, USA.
  • 8 Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore, 560099, India.
  • 9 Discovery Immunology, Bristol Myers Squibb, 250 Water St, Cambridge, MA, 02141, USA. scwilson@gmail.com.
PMID: 40595544 DOI: 10.1038/s41467-025-60632-5
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.

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