The growing arsenal of ATP-competitive and allosteric inhibitors of BCR-ABL

Cancer Res. 2012 Oct 1;72(19):4890-5. doi: 10.1158/0008-5472.CAN-12-1276. Epub 2012 Sep 21.


The BCR-ABL fusion kinase is the driving mutation of chronic myelogenous leukemias and is also expressed in a subset of acute lymphoblastic leukemias. Recent advances in elucidating the structure, regulation, and signaling of BCR-ABL have led to the identification of allosteric sites that are distant from the ATP-binding pocket and are critical for BCR-ABL-dependent oncogenic transformation. Here, we review the available data regarding the molecular mechanism of action and the specificity of ATP-competitive tyrosine kinase inhibitors targeting BCR-ABL. In addition, we discuss how targeting of allosteric sites could provide new opportunities to inhibit resistant BCR-ABL mutants, either alone or in combination with conventional ATP-competitive inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Allosteric Site / drug effects
  • Allosteric Site / genetics
  • Binding, Competitive / drug effects
  • Fusion Proteins, bcr-abl / chemistry
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism*
  • Humans
  • Models, Molecular
  • Mutation
  • Protein Binding / drug effects
  • Protein Kinase Inhibitors / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary


  • Protein Kinase Inhibitors
  • Adenosine Triphosphate
  • Fusion Proteins, bcr-abl