International Journal of Hematology

, Volume 83, Issue 4, pp 294–300 | Cite as

The Second Generation of BCR-ABL Tyrosine Kinase Inhibitors

  • Tetsuzo Tauchi
  • Kazuma Ohyashiki
Progress in Hematology


Imatinib was developed as the first molecularly targeted therapy to specifically inhibit the BCR-ABL kinase in Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML). Because of the excellent hematologic and cytogenetic responses, imatinib has moved toward first-line treatment for newly diagnosed CML. However, the emergence of resistance to imatinib remains a major problem in the treatment of Ph-positive leukemia. Several mechanisms of imatinib resistance have been identified, including BCR-ABL gene amplification that leads to overexpression of the BCR-ABL protein, point mutations in the BCR-ABL kinase domain that interfere with imatinib binding, and point mutations outside of the kinase domain that allosterically inhibit imatinib binding to BCR-ABL.The need for alternative or additional treatment for imatinib-resistant BCR-ABL-positive leukemia has guided the way to the design of a second generation of targeted therapies, which has resulted mainly in the development of novel small-molecule inhibitors such as AMN107, dasatinib, NS-187, and ON012380. The major goal of these efforts is to create new compounds that are more potent than imatinib and/or more effective against imatinib-resistant BCR-ABL clones. In this review, we discuss the next generation of BCR-ABL kinase inhibitors for overcoming imatinib resistance.

Key words

BCR-ABL Tyrosine kinase inhibitor SRC Resistance 


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Copyright information

© The Japanese Society of Hematology 2006

Authors and Affiliations

  1. 1.First Department of Internal MedicinTokyo Medical UniversityTokyoJapan

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