Novel IKK inhibitors: beta-carbolines

Bioorg Med Chem Lett. 2003 Jul 21;13(14):2419-22. doi: 10.1016/s0960-894x(03)00408-6.

Abstract

Inhibitors of IkappaB kinase (IKK) have long been sought as specific regulators of NF-kappaB. A screening effort of the endogenous IKK complex allowed us to identify 5-bromo-6-methoxy-beta-carboline as a nonspecific IKK inhibitor. Optimization of this beta-carboline natural product derivative resulted in a novel class of selective IKK inhibitors with IC(50)s in the nanomolar range. In addition, we show that one of these beta-carboline analogues inhibits the phosphorylation of IkappaBalpha and subsequent activation of NF-kappaB in whole cells, as well as blocking TNF-alpha release in LPS-challenged mice.

MeSH terms

  • Blotting, Western
  • Carbolines / chemical synthesis*
  • Carbolines / pharmacology*
  • Electrophoretic Mobility Shift Assay
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • HeLa Cells
  • Humans
  • I-kappa B Kinase
  • Precipitin Tests
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Carbolines
  • Enzyme Inhibitors
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human