October 4, 2023 12:20 pm
October 4, 2023 1:10 pm
The Development of STING Antagonists for the Treatment of Lupus and ALS
Paul Thompson
Professor and Director of Chemical Biology
University of Massachusetts Medical School
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 auto-inflammatory diseases such as Aicardi-Goutières syndrome (AGS) and STING associated vasculopathy with onset in infancy (SAVI). Significant efforts have therefore focused on developing STING inhibitors. Herein we report that the BB-Cl-amidine, a Protein Arginine Deiminase inhibitor, inhibits STING-dependent signaling in the nanomolar range both in vitro and in vivo. We further report the design and synthesis of analogs with higher potency and proteome-wide selectivity. These compounds include LB244, which displays nanomolar potency and inhibits STING signaling via the modification of C292. In summary, our data identify novel chemical entities that inhibit STING signaling and provide a novel scaffold for the development of therapeutics for treating STING-dependent inflammatory diseases.