STING inhibitors target the cyclic dinucleotide binding pocket

TLDR

Cytosolic DNA activates cGAS‑STING signaling, triggering interferon and inflammatory responses that defend against infection and cancer, but aberrant self‑DNA or gain‑of‑function STING mutations cause excessive type I interferons and fatal autoimmune disease. In silico docking identified the potent STING antagonist SN‑011, which binds the CDN‑binding pocket of STING with higher affinity than endogenous 2′3′‑cGAMP. SN‑011 locks STING in an open inactive conformation, suppresses interferon and cytokine induction from multiple activators, is well tolerated in Trex1‑/‑ mice, reduces inflammation and autoimmunity, prevents death, and represents a promising lead for STING‑driven disease.

Abstract

Cytosolic DNA activates cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling, which triggers interferon and inflammatory responses that help defend against microbial infection and cancer. However, aberrant cytosolic self-DNA in Aicardi-Goutière's syndrome and constituently active gain-of-function mutations in STING in STING-associated vasculopathy with onset in infancy (SAVI) patients lead to excessive type I interferons and proinflammatory cytokines, which cause difficult-to-treat and sometimes fatal autoimmune disease. Here, in silico docking identified a potent STING antagonist SN-011 that binds with higher affinity to the cyclic dinucleotide (CDN)-binding pocket of STING than endogenous 2'3'-cGAMP. SN-011 locks STING in an open inactive conformation, which inhibits interferon and inflammatory cytokine induction activated by 2'3'-cGAMP, herpes simplex virus type 1 infection, Trex1 deficiency, overexpression of cGAS-STING, or SAVI STING mutants. In Trex1-/- mice, SN-011 was well tolerated, strongly inhibited hallmarks of inflammation and autoimmunity disease, and prevented death. Thus, a specific STING inhibitor that binds to the STING CDN-binding pocket is a promising lead compound for STING-driven disease.