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

作者：Wei**erg Ellen; Manley Paul W; Cowan Jacob Sandra W; Hochhaus Andreas; Griffin James D^*

来源：Nature Reviews Cancer, 2007, 7(5): 345-U5.

DOI：10.1038/nrc2126

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 imatinibresistant 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.

• 出版日期2007-5