Related Experiment Video

Updated: Jan 13, 2026

Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells
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Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells

Published on: May 22, 2014

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LMT2368 (1-(4-Chlorophenyl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)urea) Negatively Regulates Inflammation by

Thai Uy Nguyen1, Su Jeong Kwon2, Sunghoon Hurh1

  • 1Department of Biomedical Science, College of Medicine, Korea University, Seoul 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.

Pharmaceutics
|October 29, 2025
PubMed

Insights

A novel urea-based compound, LMT2368, effectively inhibits NLRP3 inflammasome activation and reduces inflammation in preclinical models. This discovery offers a promising, safer therapeutic candidate for inflammatory diseases.

Area of Science:

  • Immunology
  • Pharmacology
  • Medicinal Chemistry

Background:

  • NLRP3 inflammasome activation is a key driver in inflammatory diseases, making it a therapeutic target.
  • Existing NLRP3 inhibitors like MCC950 face challenges due to toxicity, creating a need for safer alternatives.

Purpose of the Study:

  • To identify and characterize LMT2368, a novel urea-based inhibitor of NLRP3 inflammasome activation.
  • To evaluate the efficacy and safety profile of LMT2368 in preclinical models of inflammation.

Main Methods:

  • Screening of urea-based derivatives to identify LMT2368.
  • Biolayer interferometry and molecular docking to assess NLRP3 binding.
  • In vitro assays using LPS-primed macrophages to measure IL-1β secretion, caspase-1 activation, NF-κB signaling, ASC oligomerization, and pyroptosis.
  • In vivo studies using a murine model of LPS-induced acute lung injury.

Main Results:

  • LMT2368 directly binds to the NLRP3 NACHT domain with superior affinity compared to MCC950.
  • LMT2368 dose-dependently suppresses IL-1β secretion and caspase-1 activation in macrophages without impacting NF-κB signaling.
  • LMT2368 inhibits ASC oligomerization and pyroptosis, demonstrating a favorable safety profile (CC50 > 50 μM).
  • In vivo, LMT2368 significantly reduced immune cell infiltration, pro-inflammatory cytokine release, and preserved lung tissue in an acute lung injury model.
  • LMT2368 exhibits selectivity for NLRP3 inhibition, not affecting TNF-α/IL-6 production during TLR4 priming.

Conclusions:

  • LMT2368 is a potent and selective NLRP3 inhibitor with a promising safety profile.
  • These findings establish LMT2368 as a lead compound for developing safer therapeutics for inflammasome-driven diseases.
Keywords:
IL-1βLMT2368NLRP3acute lung injuryinflammasome

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