Novel IKK inhibitors: β-carbolines

https://doi.org/10.1016/S0960-894X(03)00408-6Get rights and content

Abstract

Inhibitors of IκB kinase (IKK) have long been sought as specific regulators of NF-κB. A screening effort of the endogenous IKK complex allowed us to identify 5-bromo-6-methoxy-β-carboline as a nonspecific IKK inhibitor. Optimization of this β-carboline natural product derivative resulted in a novel class of selective IKK inhibitors with IC50s in the nanomolar range. In addition, we show that one of these β-carboline analogues inhibits the phosphorylation of IκBα and subsequent activation of NF-κB in whole cells, as well as blocking TNF-α release in LPS-challenged mice.

β-Carboline 1 was identified as a nonselective IκB kinase inhibitor. Optimization of this β-carboline natural product derivative resulted in a novel class of selective IKK inhibitors with IC50s in the nanomolar range and with biological activities in whole cells and in vivo.

  1. Download : Download full-size image

Section snippets

Acknowledgements

The authors are grateful to Olaf Ritzeler and Andreas Batzer of Aventis, Frankfurt for scientific discussions.

References (19)

  • B.H Kwok et al.

    Chem. Biol.

    (2001)
  • G.W Peet et al.

    J. Biol. Chem.

    (1999)
  • Y Yamamoto et al.

    J. Biol. Chem.

    (1999)
  • C.K Weber et al.

    Gastroenterology

    (2000)
  • M.A Read et al.

    Immunity

    (1995)
  • T Hideshima et al.

    J. Biol. Chem.

    (2002)
  • Y Yamamoto et al.

    J. Clin. Invest.

    (2001)
  • C Jobin et al.

    J. Immunol.

    (1999)
  • F Yang et al.

    Mol. Pharmacol.

    (2001)
There are more references available in the full text version of this article.

Cited by (241)

  • Modified peptides and organic metabolites of cyanobacterial origin with antiplasmodial properties

    2024, International Journal for Parasitology: Drugs and Drug Resistance
View all citing articles on Scopus
View full text