Development of LB244, an Irreversible STING Antagonist

The cGMP-AMP Synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway plays a critical role in sensing dsDNA localized to the cytosol, resulting in the activation of a robust inflammatory response. While cGAS-STING signaling is essential for antiviral immunity, aberrant STING activation is observed in amyotrophic lateral sclerosis (ALS), lupus, and autoinflammatory diseases such as Aicardi-Goutie`res syndrome (AGS) and STING associated vasculopathy with onset in infancy (SAVI). Significant efforts have therefore focused on the development of STING inhibitors. In a concurrent submission, we reported that BB-Cl-amidine inhibits STING-dependent signaling in the nanomolar range, both in vitro and in vivo. Considering this discovery, we sought to generate analogs with higher potency and proteome-wide selectivity. Herein, we report the development of LB244, which displays nanomolar potency and inhibits STING signaling with markedly enhanced proteome-wide selectivity. Moreover, LB244 mirrored the efficacy of BB-Cl-amidine in vivo. In summary, our data identify novel chemical entities that inhibit STING signaling and provide a scaffold for the development of therapeutics for treating STING-dependent inflammatory diseases.

Automated summary

The cGMP-AMP Synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway is crucial for detecting cytosolic dsDNA and triggering inflammatory response. Aberrant STING activation is associated with diseases such as ALS, lupus, AGS, and SAVI. In this study, we developed LB244 as a highly potent and selective inhibitor of STING signaling, which showed efficacy comparable to BB-Cl-amidine in vivo. These findings suggest a potential therapeutic approach for STING-dependent inflammatory diseases.