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Development of LB244, an Irreversible STING Antagonist.
Barasa, Leonard; Chaudhuri, Sauradip; Zhou, Jeffrey Y; Jiang, Zhaozhao; Choudhary, Shruti; Green, Robert Madison; Wiggin, Elenore; Cameron, Michael; Humphries, Fiachra; Fitzgerald, Katherine A; Thompson, Paul R.
Afiliación
  • Barasa L; Program in Chemical Biology, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, United States.
  • Chaudhuri S; Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, United States.
  • Zhou JY; Program in Chemical Biology, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, United States.
  • Jiang Z; Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, United States.
  • Choudhary S; Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, United States.
  • Green RM; Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, United States.
  • Wiggin E; Program in Chemical Biology, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, United States.
  • Cameron M; Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, United States.
  • Humphries F; Program in Chemical Biology, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, United States.
  • Fitzgerald KA; Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, United States.
  • Thompson PR; Program in Chemical Biology, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, United States.
J Am Chem Soc ; 145(37): 20273-20288, 2023 09 20.
Article en En | MEDLINE | ID: mdl-37695732
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-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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Autoinmunes del Sistema Nervioso / Esclerosis Amiotrófica Lateral Límite: Humans Idioma: En Revista: J Am Chem Soc Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Autoinmunes del Sistema Nervioso / Esclerosis Amiotrófica Lateral Límite: Humans Idioma: En Revista: J Am Chem Soc Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos