Flying under the radar: the new wave of BCR-ABL inhibitors.
The introduction of the BCR-ABL kinase inhibitor imatinib mesylate (Gleevec; Novartis) revolutionized the treatment of chronic myeloid leukaemia (CML). However, most patients with CML receiving imatinib still harbour molecular residual disease and some develop resistance associated with ABL kinase domain mutations. The second-generation BCR-ABL inhibitors nilotinib (Tasigna; Novartis) and dasatinib (Sprycel; Bristol-Myers Squibb) have shown significant activity after imatinib failure in clinical trials, but still face similar obstacles to imatinib, including negligible activity against the frequent BCR-ABL T315I mutation and modest effects in advanced phases of CML. Various medicinal chemistry efforts, in part aided by structural studies of the ABL kinase-imatinib complex have resulted in the synthesis of a new generation of BCR-ABL inhibitors, some of which have shown encouraging preliminary activity in clinical trials, including against T315I mutants. Here, we discuss these emerging therapies, which have the potential to improve the outcome of patients with CML.
Quintás-Cardama
Alfonso
A
Department of Leukemia, Unit 428, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas 77030, USA. aquintas@mdanderson.org
Kantarjian
Hagop
H
Cortes
Jorge
J
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology; D008958:Models, Molecular; D017354:Point Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl