Selective inhibitors of type I receptor kinase block cellular transforming growth factor-beta signaling

Biochem Pharmacol. 2004 Jul 1;68(1):41-50. doi: 10.1016/j.bcp.2004.03.011.


Transforming growth factor (TGFbeta) is a 25-kDa dimeric polypeptide that plays a key role in a variety of physiological processes and disease states. Blocking TGFbeta signaling represents a potentially powerful and conceptually novel approach to the treatment of disorders in which the signaling pathway is constitutively activated, such as cancer, chronic inflammation with fibrosis and select immune disorders. In this paper, we describe the biological properties of a novel series of quinazoline-derived inhibitors of the type I transforming growth factor receptor kinase (TbetaKIs) that bind to the ATP-binding site and keep the kinase in its inactive conformation. These compounds effectively inhibited TGFbeta-induced Smad2 phosphorylation in cultured cells in vitro with an IC(50) between 20 and 300 nM. Moreover, TbetaKIs were able to broadly block TGFbeta-induced reporter gene activation. Finally, TbetaKIs inhibited TGFbeta-mediated growth inhibition of normal murine mammary epithelial cells (NMuMG) and mink lung epithelial cells (Mv1Lu), and TGFbeta-induced epithelial-mesenchymal transdifferentiation (EMT) of NMuMG cells. Thus, these chemical TbetaKIs have the potential to be further developed as anti-cancer and -fibrosis agents. In addition, they represent valuable new tools for dissecting the biochemical mechanisms of TGFbeta signal transduction and understanding the role of TGFbeta signaling pathways in different physiological and disease processes.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Division / drug effects
  • DNA-Binding Proteins / metabolism
  • Drug Interactions
  • Epithelial Cells / drug effects
  • Gene Expression Regulation / drug effects
  • Humans
  • Mice
  • Peptides / pharmacology*
  • Phosphorylation / drug effects
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • Smad2 Protein
  • Trans-Activators / metabolism
  • Transcriptional Activation
  • Transforming Growth Factor beta / pharmacology*
  • Tumor Cells, Cultured


  • DNA-Binding Proteins
  • Peptides
  • Receptors, Transforming Growth Factor beta
  • SMAD2 protein, human
  • Smad2 Protein
  • Smad2 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta