SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice

Cancer Res. 2003 Jan 15;63(2):375-81.

Abstract

Constitutive tyrosine kinase activity of Bcr-Abl promotes proliferation and survival of chronic myelogenous leukemia (CML) cells. Inhibition of Bcr-Abl tyrosine kinase activity or signaling proteins activated by Bcr-Abl in CML cells blocks proliferation and causes apoptotic cell death. The selective Abl kinase inhibitor, STI-571 (marketed as Gleevec), is toxic to CML cells in culture, causes regression of CML tumors in nude mice, and is currently used to treat CML patients. Here we describe a p.o. active, dual Src/Abl kinase inhibitor with potent antiproliferative activity against CML cells in culture. This 4-anilino-3-quinolinecarbonitrile (SKI-606) ablates tyrosine phosphorylation of Bcr-Abl in CML cells and of v-Abl expressed in fibroblasts. SKI-606 inhibits phosphorylation of cellular proteins, including STAT5, at concentrations that inhibit proliferation in CML cells. Phosphorylation of the autoactivation site of the Src family kinases Lyn and/or Hck is also reduced by treatment with SKI-606. Once daily oral administration of this compound at 100 mg/kg for 5 days causes complete regression of large K562 xenografts in nude mice.

MeSH terms

  • Aniline Compounds / pharmacology*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Division / drug effects
  • Cell Survival / drug effects
  • DNA-Binding Proteins / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Fusion Proteins, bcr-abl
  • Humans
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Mice
  • Milk Proteins*
  • Nitriles / pharmacology*
  • Phosphorylation / drug effects
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
  • Quinolines / pharmacology*
  • STAT5 Transcription Factor
  • Trans-Activators / metabolism
  • Xenograft Model Antitumor Assays
  • src-Family Kinases / antagonists & inhibitors*
  • src-Family Kinases / metabolism

Substances

  • Aniline Compounds
  • Antineoplastic Agents
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Milk Proteins
  • Nitriles
  • Quinolines
  • STAT5 Transcription Factor
  • Trans-Activators
  • bosutinib
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • Proto-Oncogene Proteins c-abl
  • src-Family Kinases