Characterization of YM-90709 as a novel antagonist which inhibits the binding of interleukin-5 to interleukin-5 receptor

Int Immunopharmacol. 2002 Nov;2(12):1693-702. doi: 10.1016/s1567-5769(02)00191-1.

Abstract

Interleukin-5 (IL-5) plays an important role in the activation of eosinophils in allergic inflammation including asthma and atopic dermatitis. A newly synthesized compound, YM-90709, 2,3-dimethoxy-6,6-dimethyl-5,6-dihydrobenzo[7,8]indolizino [2,3-b]quinoxaline, is reported here to inhibit the binding of IL-5 to its receptor on peripheral human eosinophils and butyric acid-treated eosinophilic HL-60 clone 15 cells, with IC50 values of 1.0 and 0.57 microM, respectively. In contrast, YM-90709 did not affect the binding of granulocyte-macrophage colony-stimulating factor (GM-CSF) to its receptor on eosinophils and eosinophilic HL-60 clone 15 cells. In functional assays, YM-90709 inhibited IL-5-prolonged eosinophil survival with an IC50 value of 0.45 microM and did not affect the GM-CSF-prolonged eosinophil survival. Furthermore, YM-90709 inhibited the IL-5-induced but not GM-CSF-induced tyrosine phosphorylation of Janus kinase 2 (JAK2) in eosinophilic HL-60 clone 15 cells. These results indicate that YM-90709 is a novel IL-5 inhibitor which selectively blocks the binding of IL-5 to the IL-5 receptor (IL-5R).

MeSH terms

  • Anti-Allergic Agents / pharmacology*
  • Cell Survival / drug effects
  • Eosinophils / cytology
  • Eosinophils / drug effects
  • Eosinophils / metabolism
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • HL-60 Cells
  • Humans
  • Indoles / pharmacology*
  • Inhibitory Concentration 50
  • Interleukin-5 / antagonists & inhibitors*
  • Interleukin-5 / metabolism
  • Interleukin-5 / pharmacology
  • Janus Kinase 2
  • Phosphorylation / drug effects
  • Phosphotyrosine / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins*
  • Quinoxalines / pharmacology*
  • Receptors, Interleukin / antagonists & inhibitors*
  • Receptors, Interleukin / metabolism
  • Receptors, Interleukin-5

Substances

  • 2,3-dimethoxy-6,6-dimethyl-5,6-dihydrobenzo(7,8)indolizino (2,3-b)quinoxaline
  • Anti-Allergic Agents
  • Indoles
  • Interleukin-5
  • Proto-Oncogene Proteins
  • Quinoxalines
  • Receptors, Interleukin
  • Receptors, Interleukin-5
  • Phosphotyrosine
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Protein-Tyrosine Kinases
  • JAK2 protein, human
  • Janus Kinase 2