Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia.
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.
Weisberg
Ellen
E
Dana Farber Cancer Institute, Mayer 540, 44 Binney Street, Boston, MA 02115, USA.
Manley
Paul W
PW
Cowan-Jacob
Sandra W
SW
Hochhaus
Andreas
A
Griffin
James D
JD
D000970:Antineoplastic Agents / Q000494:pharmacology; D064127:Aurora Kinases; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases