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Nat Rev Cancer. 2007 May;7(5):345-56.

Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia.

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  • 1Dana Farber Cancer Institute, Mayer 540, 44 Binney Street, Boston, MA 02115, USA.


Imatinib, a small-molecule ABL kinase inhibitor, is a highly effective therapy for early-phase chronic myeloid leukaemia (CML), which has constitutively active ABL kinase activity owing to the expression of the BCR-ABL fusion protein. However, there is a high relapse rate among advanced- and blast-crisis-phase patients owing to the development of mutations in the ABL kinase domain that cause drug resistance. Several second-generation ABL kinase inhibitors have been or are being developed for the treatment of imatinib-resistant CML. Here, we describe the mechanism of action of imatinib in CML, the structural basis of imatinib resistance, and the potential of second-generation BCR-ABL inhibitors to circumvent resistance.

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