The specificities of small molecule inhibitors of the TGFß and BMP pathways

Cell Signal. 2011 Nov;23(11):1831-42. doi: 10.1016/j.cellsig.2011.06.019. Epub 2011 Jun 29.

Abstract

Small molecule inhibitors of type 1 receptor serine threonine kinases (ALKs1-7), the mediators of TGFß and BMP signals, have been employed extensively to assess their physiological roles in cells and organisms. While all of these inhibitors have been reported as "selective" inhibitors of specific ALKs, extensive specificity tests against a wide array of protein kinases have not been performed. In this study, we examine the specificities and potencies of the most frequently used small molecule inhibitors of the TGFß pathway (SB-431542, SB-505124, LY-364947 and A-83-01) and the BMP pathway (Dorsomorphin and LDN-193189) against a panel of up to 123 protein kinases covering a broad spectrum of the human kinome. We demonstrate that the inhibitors of the TGFß pathway are relatively more selective than the inhibitors of the BMP pathway. Based on our specificity and potency profile and published data, we recommend SB-505124 as the most suitable molecule for use as an inhibitor of ALKs 4, 5 and 7 and the TGFß pathway. We do not recommend Dorsomorphin, also called Compound C, for use as an inhibitor of the BMP pathway. Although LDN-193189, a Dorsomorphin derivative, is a very potent inhibitor of ALK2/3 and the BMP-pathway, we found that it potently inhibited a number of other protein kinases at concentrations sufficient to inhibit ALK2/3 and its use as a selective BMP-pathway inhibitor has to be considered cautiously. Our observations have highlighted the need for caution when using these small molecule inhibitors to assess the physiological roles of BMP and TGFß pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Automation, Laboratory
  • Blotting, Western
  • Bone Morphogenetic Proteins / metabolism*
  • Cells, Cultured
  • Electrophoresis, Polyacrylamide Gel
  • High-Throughput Screening Assays*
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / enzymology*
  • Phosphorylation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases* / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases* / genetics
  • Protein-Serine-Threonine Kinases* / metabolism
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Recombinant Proteins* / antagonists & inhibitors
  • Recombinant Proteins* / genetics
  • Recombinant Proteins* / metabolism
  • Sensitivity and Specificity
  • Signal Transduction / drug effects*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Transforming Growth Factor beta / metabolism*

Substances

  • Bone Morphogenetic Proteins
  • LDN 193189
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Recombinant Proteins
  • Small Molecule Libraries
  • Transforming Growth Factor beta
  • dorsomorphin
  • Protein-Serine-Threonine Kinases