Orthosteric STING inhibition elucidates molecular correction of SAVI STING

STING is broadly implicated in diseases ranging from cancer, autoimmune disease, neurodegeneration to rare, monogenic diseases. 1 Early drug discovery campaigns focused on STING activation as a promising platform for cancer immunotherapy yet failed in multiple clinical trials due to lack of efficacy thus far. 2 Current research and development activities concentrate on STING inhibition for treating autoimmune disease and neuroinflammation. 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. 3 Here we leverage an orthosteric STING activator and inhibitor from the same chemical series to discover that STING M271 is a critical residue for molecular activation. The M271 CH3 NMR chemical shifts reveal a unique molecular signature for pharmacological or genetically driven activation and inhibition that is not captured by x-ray crystallography. Additionally, M271 directly interacts with the most common SAVI mutation, V155M, and using an orthosteric STING inhibitor, we show partial rescue and molecular correction of STING V155M. Finally, these data present insights into therapeutic STING molecular correction for treating SAVI patients. Our results elucidate an unappreciated structural interaction critical for STING modulation that could be utilized as a molecular diagnostic tool for drug discovery. Furthermore, we demonstrate for the first time how the therapeutic requirements of a molecular corrector differ from an orthosteric STING inhibitor, and why this is important for the SAVI disease population.