Allosteric inhibitors of Bcr-abl-dependent cell proliferation

Nat Chem Biol. 2006 Feb;2(2):95-102. doi: 10.1038/nchembio760. Epub 2006 Jan 15.


Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated tyrosine kinase activity. Encouraged by the clinical validation of Bcr-abl as the target for the treatment of CML by imatinib, we sought to identify pharmacological agents that could target this kinase by a distinct mechanism. We report the discovery of a new class of Bcr-abl inhibitors using an unbiased differential cytotoxicity screen of a combinatorial kinase-directed heterocycle library. Compounds in this class (exemplified by GNF-2) show exclusive antiproliferative activity toward Bcr-abl-transformed cells, with potencies similar to imatinib, while showing no inhibition of the kinase activity of full-length or catalytic domain of c-abl. We propose that this new class of compounds inhibits Bcr-abl kinase activity through an allosteric non-ATP competitive mechanism.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Benzamides
  • Cell Line
  • Cell Line, Transformed
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Fusion Proteins, bcr-abl / chemistry
  • Fusion Proteins, bcr-abl / metabolism
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Mice
  • Piperazines / pharmacology*
  • Protein Binding
  • Protein Conformation
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyrimidines / pharmacology*


  • Antineoplastic Agents
  • Benzamides
  • GNF-2 compound
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl

Associated data

  • PubChem-Substance/7980923
  • PubChem-Substance/7980924
  • PubChem-Substance/7980925
  • PubChem-Substance/7980926
  • PubChem-Substance/7980927
  • PubChem-Substance/7980928
  • PubChem-Substance/7980929
  • PubChem-Substance/7980930
  • PubChem-Substance/7980931
  • PubChem-Substance/7982027