The second generation of BCR-ABL tyrosine kinase inhibitors.
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.
Tauchi
Tetsuzo
T
First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan. tauchi@tokyo-med.ac.jp
Ohyashiki
Kazuma
K
D000494:Allosteric Regulation / Q000187:drug effects / Q000235:genetics; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D016044:Fusion Proteins, bcr-abl; D005784:Gene Amplification / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D009154:Mutation; D010677:Philadelphia Chromosome; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D017434:Protein Structure, Tertiary / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl