Photochemical preparation of a pyridone containing tetracycle: a Jak protein kinase inhibitor

Bioorg Med Chem Lett. 2002 Apr 22;12(8):1219-23. doi: 10.1016/s0960-894x(02)00106-3.

Abstract

Jak3 is a protein tyrosine kinase that is associated with the shared gamma chain of receptors for cytokines IL2, IL4, IL7, IL9, and IL13. We have discovered that a pyridone-containing tetracycle (6) may be prepared from trisubstituted imidazole (5) in high yield by irradiation with >350 nm light. Compound 6 inhibits Jak3 with K(I)=5 nM; it also inhibits Jak family members Tyk2 and Jak2 with IC(50)=1 nM and murine Jak1with IC(50)=15 nM. Compound 6 was tested as an inhibitor of 21 other protein kinases; it inhibited these kinases with IC(50)s ranging from 130 nM to >10 microM. Compound 6 also blocks IL2 and IL4 dependent proliferation of CTLL cells and inhibits the phosphorylation of STAT5 (an in vivo substrate of the Jak family) as measured by Western blotting.

MeSH terms

  • Animals
  • Cell Division / drug effects
  • DNA-Binding Proteins / metabolism
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Interleukin-2 / antagonists & inhibitors
  • Interleukin-2 / pharmacology
  • Interleukin-4 / antagonists & inhibitors
  • Interleukin-4 / pharmacology
  • Janus Kinase 3
  • Mice
  • Milk Proteins*
  • Phosphorylation
  • Photochemistry
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyridones / chemistry*
  • STAT5 Transcription Factor
  • Trans-Activators / metabolism

Substances

  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Interleukin-2
  • Milk Proteins
  • Pyridones
  • STAT5 Transcription Factor
  • Trans-Activators
  • Interleukin-4
  • Protein-Tyrosine Kinases
  • Jak3 protein, mouse
  • Janus Kinase 3