A molecular glue induces aberrant STING oligomerization and inhibits autoinflammatory diseases.

Dysregulated activation of the stimulator of interferon genes (STING) pathway underlies various inflammatory and autoimmune pathologies. Since STING oligomerization is fundamental to its biological function, targeted modulation of this polymerization process presents a promising therapeutic approach. However, achieving precise control over STING polymerization has remained a significant challenge. In this study, we report that benzofuran derivatives serve as molecular glues to potently inhibit STING activity by inducing its aberrant oligomerization. Structural analyses demonstrated that these compounds function as glues, promoting an unconventional "head-to-head" STING dimerization configuration that differs markedly from the linear polymers formed during canonical pathway activation. These compounds exhibit potent inhibitory activity against different STING isoforms activated by 2',3'-cGAMP, dsDNA, gain-of-function SAVI-associated STING mutant, and herpes simplex virus type 1 (HSV-1) infection. DDO-6513 downregulates the expression of type I interferons (IFN-I), IFN-stimulated genes (ISGs) and pro-inflammatory cytokines in clinical samples isolated from patients with STING-associated autoimmune disorders, including Aicardi-Goutières syndrome (AGS), systemic lupus erythematosus (SLE), and dermatomyositis (DM). In vivo, DDO-7432 displays desirable drug-like properties, and exerts remarkable anti-inflammatory efficacy in murine myositis disease models. Our findings demonstrate that modulating protein oligomerization via molecular glues can effectively disrupt signal transduction, providing novel insights into therapeutic strategies for oligomerization-dependent targets.