The ALK-5 inhibitor A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-beta

Cancer Sci. 2005 Nov;96(11):791-800. doi: 10.1111/j.1349-7006.2005.00103.x.


Transforming growth factor (TGF)-beta signaling facilitates tumor growth and metastasis in advanced cancer. Use of inhibitors of TGF-beta signaling may thus be a novel strategy for the treatment of patients with such cancer. In this study, we synthesized and characterized a small molecule inhibitor, A-83-01, which is structurally similar to previously reported ALK-5 inhibitors developed by Sawyer et al. (2003) and blocks signaling of type I serine/threonine kinase receptors for cytokines of the TGF-beta superfamily (known as activin receptor-like kinases; ALKs). Using a TGF-beta-responsive reporter construct in mammalian cells, we found that A-83-01 inhibited the transcriptional activity induced by TGF-beta type I receptor ALK-5 and that by activin type IB receptor ALK-4 and nodal type I receptor ALK-7, the kinase domains of which are structurally highly related to those of ALK-5. A-83-01 was found to be more potent in the inhibition of ALK5 than a previously described ALK-5 inhibitor, SB-431542, and also to prevent phosphorylation of Smad2/3 and the growth inhibition induced by TGF-beta. In contrast, A-83-01 had little or no effect on bone morphogenetic protein type I receptors, p38 mitogen-activated protein kinase, or extracellular regulated kinase. Consistent with these findings, A-83-01 inhibited the epithelial-to-mesenchymal transition induced by TGF-beta, suggesting that A-83-01 and related molecules may be useful for preventing the progression of advanced cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / antagonists & inhibitors*
  • Activin Receptors, Type I / physiology
  • Animals
  • Humans
  • Lung / cytology
  • Mink
  • Neoplasms / drug therapy
  • Neoplasms / pathology
  • Protein-Serine-Threonine Kinases
  • Pyrazoles / pharmacology*
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Receptors, Transforming Growth Factor beta / physiology
  • Signal Transduction / drug effects
  • Smad Proteins / metabolism
  • Smad Proteins / physiology
  • Thiocarbamates / pharmacology*
  • Thiosemicarbazones
  • Transcription, Genetic / drug effects
  • Transforming Growth Factor beta / physiology*
  • Tumor Cells, Cultured


  • A-83-01
  • Pyrazoles
  • Receptors, Transforming Growth Factor beta
  • Smad Proteins
  • Thiocarbamates
  • Thiosemicarbazones
  • Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human