SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7

Mol Pharmacol. 2004 Mar;65(3):744-52. doi: 10.1124/mol.65.3.744.

Abstract

Clinically, there is a great need for small molecule inhibitors that could control pathogenic effects of transforming growth factor (TGF-beta) and/or modulate effects of TGF-beta in normal responses. Inhibition of TGF-beta signaling would be predicted to enhance re-epithelialization of cutaneous wounds and reduce scarring fibrosis. Selective small molecule inhibitors of the TGF-beta signaling pathway developed for therapeutics will also be powerful tools in experimentally dissecting this complex pathway, especially its cross-talk with other signaling pathways. In this study, we characterized 2-(5-benzo[1,3]dioxol-5-yl-2-tert-butyl-3H-imidazol-4-yl)-6-methylpyridine hydrochloride (SB-505124), a member of a new class of small molecule inhibitors related to imidazole inhibitors of p38, which inhibit the TGF-beta type I receptor serine/threonine kinase known as activin receptor-like kinase (ALK) 5. We demonstrate that this compound selectively and concentration-dependently inhibits ALK4-, ALK5-, and ALK 7-dependent activation of downstream cytoplasmic signal transducers, Smad2 and Smad3, and of TGF-beta-induced mitogen-activated protein kinase pathway components but does not alter ALK1, ALK2, ALK3 or ALK6-induced Smad signaling. SB-505124 also blocks more complex endpoints of TGF-beta action, as evidenced by its ability to abrogate cell death caused by TGF-beta1 treatment. SB-505124 is three to five times more potent than a related ALK5 inhibitor described previously, SB-431542.

MeSH terms

  • Activin Receptors, Type I / antagonists & inhibitors*
  • Activins / pharmacology
  • Animals
  • Benzamides / pharmacology
  • COS Cells
  • Cell Death / drug effects
  • DNA-Binding Proteins / metabolism
  • Dioxoles / pharmacology
  • Drug Interactions
  • Genes, Reporter
  • Humans
  • Mitogen-Activated Protein Kinases / metabolism
  • Protein Serine-Threonine Kinases
  • Proteins*
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Smad Proteins
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Tumor Cells, Cultured

Substances

  • 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
  • Benzamides
  • DNA-Binding Proteins
  • Dioxoles
  • Proteins
  • Receptors, Transforming Growth Factor beta
  • Smad Proteins
  • Trans-Activators
  • Transforming Growth Factor beta
  • Activins
  • Protein Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • ACVR1B protein, human
  • ACVR1C protein, human
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human