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Nitrofuran-Based STING Inhibitors.

Leonard Barasa1,2, Leo DeOrsey1,2, Maeve D O'Reilly1,2

  • 1Program in Chemical Biology, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, United States.

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Summary
This summary is machine-generated.

New STING inhibitors, UM-242 and UM-259, were developed to treat STING-dependent inflammatory diseases. These compounds effectively block STING signaling, offering potential therapeutic benefits for conditions like ALS and lupus.

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Area of Science:

  • Immunology
  • Molecular Biology
  • Drug Discovery

Background:

  • The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is crucial for innate immunity against foreign DNA.
  • Dysregulated STING activation is implicated in autoimmune and autoinflammatory diseases, including amyotrophic lateral sclerosis (ALS), lupus, Aicardi-Goutières syndrome (AGS), and STING-associated vasculopathy with onset in infancy (SAVI).
  • STING antagonists are being explored as potential therapeutics for these conditions.

Purpose of the Study:

  • To optimize the potency of the STING antagonist LB244.
  • To develop novel STING inhibitors with improved efficacy and broader applicability.
  • To evaluate the potential of new compounds as therapeutic agents for STING-dependent inflammatory diseases.

Main Methods:

  • Structure-activity relationship (SAR) studies were performed to optimize LB244.
  • The developed compounds, UM-242 and UM-259, were tested for their ability to inhibit STING-dependent signaling in mouse and human cell systems.
  • Inhibition was assessed in various cell types, including primary human CD14+ monocytes, and against common human STING variants.

Main Results:

  • Optimization of LB244 led to the discovery of UM-242 and UM-259.
  • UM-242 and UM-259 demonstrated potent inhibition of both mouse and human STING signaling, comparable to LB244.
  • These novel inhibitors retained efficacy against the common human STING variant R232 and showed activity in primary human monocytes.

Conclusions:

  • UM-242 and UM-259 are novel STING antagonists with potent inhibitory activity against human and mouse STING.
  • These compounds are effective against a common human STING variant and in primary human immune cells.
  • UM-242 and UM-259 represent promising scaffolds for the development of therapeutics targeting STING-dependent inflammatory diseases.