META060 inhibits multiple kinases in the NF-kappaB pathway and suppresses LPS--mediated inflammation in vitro and ex vivo

Inflamm Res. 2009 May;58(5):229-34. doi: 10.1007/s00011-008-8162-y.


Objective: We investigated whether a novel candidate META060 targeted the inflammatory signal transduction without affecting constitutive COX-2 enzymatic activity in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We also investigated its bioavailability in humans and its anti-inflammatory effect ex vivo.

Methods: We measured prostaglandin E(2), nitric oxide, TNFalpha and IL-6 by ELISA, COX-2 protein by Western blot, NF-kappaB nuclear binding by electrophoretic mobility shift assays, and NF-kappaB activation by luciferase assay. Kinase inhibitions were measured by cell-free assays. Bioavailability was tested in 4 human subjects consuming 940 mg META060. LPS-activated TNFalpha and IL-6 were measured in peripheral blood mononuclear cells (PBMC) isolated from 1 subject up to 6 hours post administration.

Results: META060 dose-dependently inhibited prostaglandin E(2) and nitric oxide formation, COX-2 abundance, and NF-kappaB activation. In cell-free assays, META060 inhibited multiple kinases in the NF-kappaB signaling pathway, including BTK, PI3K, and GSK3. META060 was detected in the plasma of the subjects; isolated PBMC were resistant to LPS-stimulated TNFalpha and IL-6 production.

Conclusion: Without inhibiting COX-2 enzyme, META060 reduces the inflammation by inhibiting multiple kinases involved in NF-kappaB pathway, and may have potential as a safe anti-inflammatory therapeutic.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / metabolism
  • Anti-Inflammatory Agents / pharmacology*
  • Cell Line
  • Cyclooxygenase 2 / metabolism
  • Cyclopentanes / chemistry
  • Cyclopentanes / metabolism
  • Cyclopentanes / pharmacology*
  • Dinoprostone / metabolism
  • Humans
  • Inflammation* / chemically induced
  • Inflammation* / metabolism
  • Interleukin-6 / metabolism
  • Lipopolysaccharides / immunology*
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Molecular Structure
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Nitric Oxide / metabolism
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Signal Transduction* / drug effects
  • Signal Transduction* / physiology
  • Tumor Necrosis Factor-alpha / metabolism


  • Anti-Inflammatory Agents
  • Cyclopentanes
  • Interleukin-6
  • Lipopolysaccharides
  • NF-kappa B
  • Protein Kinase Inhibitors
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • 1,3-cyclopentadiene
  • Cyclooxygenase 2
  • Dinoprostone