Urea derivatives of STI571 as inhibitors of Bcr-Abl and PDGFR kinases

Bioorg Med Chem Lett. 2004 Dec 6;14(23):5793-7. doi: 10.1016/j.bmcl.2004.09.042.

Abstract

The constitutively active Abl kinase activity of the Bcr-Abl oncoprotein is causative for chronic myelogenous leukemia. Urea derivatives, structurally related to the therapeutic agent STI571, have been identified, which potently inhibit the tyrosine kinase activity of recombinant Abl. In particular a dimethylamino-aniline derivative (18) inhibited c-Abl transphosphorylation with an IC(50) value of 56 nM. Although this activity was not translated into cellular activity against the constitutively activated oncogenic Bcr-Abl, a number of compounds from this series potently inhibited cellular PDGFR autophosphorylation. It was also possible to differentiate between c-Abl and PDGFR kinase inhibition, with compound 22 being selective towards Abl and 23 selective for PDGFR.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Benzamides
  • Cell Line, Tumor
  • Genes, abl / drug effects*
  • Genes, abl / physiology
  • Humans
  • Imatinib Mesylate
  • Mice
  • Piperazines / chemistry*
  • Piperazines / pharmacology
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Protein Kinase Inhibitors / analogs & derivatives*
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors*
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Urea / analogs & derivatives*
  • Urea / pharmacology

Substances

  • Benzamides
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Imatinib Mesylate
  • Urea
  • Receptors, Platelet-Derived Growth Factor