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ortho–para-Directing Deactivators: Halogens01:24

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Halogens are ortho–para directors. They are more electronegative than carbon. Therefore, as ring substituents, they can withdraw electrons through the inductive effect and deactivate the aromatic ring towards electrophilic substitution. Halogens also have an electron-donating resonance effect on the ring, which influences the orientation of the incoming electrophile. If an electrophile attacks at the ortho or the para position, the halogen donates electrons and stabilizes the intermediate...
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The Development of UM-203, A Reversible Covalent STING Antagonist.

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.

ACS Medicinal Chemistry Letters
|January 14, 2026
PubMed
Summary

Researchers developed UM-203, a novel reversible covalent inhibitor targeting the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. This compound effectively inhibits STING signaling in human and mouse systems, offering potential for autoimmune disease therapies.

Keywords:
CytokinesOligomerizationStimulator of interferon genesTBK1Type I interferoninhibitor

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Area of Science:

  • Immunology
  • Molecular Biology
  • Drug Discovery

Background:

  • The cGAS-STING pathway is crucial for innate immunity by detecting cytosolic DNA and initiating inflammatory responses.
  • Dysregulation of the cGAS-STING pathway is implicated in various inflammatory and autoimmune diseases.
  • STING is a significant therapeutic target for managing these conditions.

Purpose of the Study:

  • To develop and characterize a novel reversible covalent inhibitor of the STING pathway.
  • To evaluate the efficacy of the inhibitor against human and mouse STING signaling.
  • To assess the inhibitor's potential as a therapeutic scaffold for STING-related diseases.

Main Methods:

  • Development of a reversible covalent inhibitor, UM-203, utilizing an alkyne-thiazole warhead.
  • Testing of UM-203's inhibitory activity in both murine and human cellular systems.
  • Assessment of UM-203's efficacy against the common human STING variant (R232) and in primary human monocytes.

Main Results:

  • UM-203 demonstrated potent inhibition of STING-dependent signaling across mouse and human models.
  • The inhibitor retained activity against the prevalent R232 human STING variant.
  • UM-203 effectively suppressed STING signaling in primary human CD14+ monocytes and showed moderate metabolic stability.

Conclusions:

  • UM-203 represents the first reversible covalent STING inhibitor developed.
  • The compound shows promise as a therapeutic scaffold for treating STING-driven inflammatory and autoimmune diseases.
  • Further development of UM-203 could lead to novel treatments for conditions associated with aberrant STING activation.