刺
干扰素基因刺激剂
化学
体内
信号转导
干扰素
药理学
细胞生物学
免疫学
生物化学
受体
医学
生物
先天免疫系统
生物技术
航空航天工程
工程类
作者
Leonard Barasa,Sauradip Chaudhuri,Jeffrey Y. Zhou,Zhaozhao Jiang,Sonal Choudhary,Robert Madison Green,Elenore Wiggin,Michael D. Cameron,Fiachra Humphries,Katherine A. Fitzgerald,Paul R. Thompson
摘要
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-Goutières 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-amidinein 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.
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