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Updated: Jun 15, 2025

High-throughput Quantitative Real-time RT-PCR Assay for Determining Expression Profiles of Types I and III Interferon Subtypes
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High-throughput Quantitative Real-time RT-PCR Assay for Determining Expression Profiles of Types I and III Interferon Subtypes

Published on: March 24, 2015

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A novel TREX1 inhibitor, VB-85680, upregulates cellular interferon responses

Stephen Flowers1, Brenda A Petronella2, Michael S McQueney1

  • 1Oncoveda, A Division of Genesis Research & Development Institute, LLC, Hamilton, New Jersey, United States of America.

Plos One
|August 23, 2024
PubMed

Insights

A novel TREX1 inhibitor, VB-85680, activates the cGAS-STING pathway by preventing DNA degradation. This enhances anti-tumor immunity, particularly when combined with DNA-generating agents.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cancer Research

Background:

  • The cGAS-STING pathway is crucial for innate immunity against cancer, mediating Type-1 Interferon (IFN) production and T cell priming.
  • Cytosolic double-stranded DNA (dsDNA) activates cyclic GMP-AMP synthase (cGAS), which signals STING (STimulator of INterferon Genes) to induce IFN-related gene expression.
  • Three-prime Repair EXonuclease 1 (TREX1) degrades cytosolic dsDNA, acting as a negative regulator of the cGAS-STING pathway and reducing IFN secretion.

Purpose of the Study:

  • To characterize the activity of VB-85680, a small-molecule inhibitor of TREX1.
  • To evaluate the potential of TREX1 inhibition to enhance STING pathway activation and anti-tumor immunity.

Main Methods:

  • In vitro enzymatic assays to assess TREX1 inhibition by VB-85680 using human and mouse cell lysates.
  • Cell-based assays to measure STING signaling activation and IFN-stimulated gene (ISG) expression in response to VB-85680 treatment.
  • Combination studies with exogenous DNA in THP1-Dual™ cells under low-serum conditions.

Main Results:

  • VB-85680 effectively inhibited TREX1 exonuclease activity in vitro.
  • Treatment with VB-85680 led to the activation of STING signaling and ISG expression in intact cells.
  • Combined treatment with VB-85680 and exogenous DNA enhanced the ISG response in THP1-Dual™ cells.

Conclusions:

  • VB-85680 is a potent TREX1 inhibitor with the capacity to activate the cGAS-STING pathway.
  • TREX1 inhibition holds promise for enhancing anti-tumor immunity, especially in combination with therapies that generate cytosolic DNA.

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