The second generation of BCR-ABL tyrosine kinase inhibitors.

Abstract

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.

• Authors: Tetsuzo Tauchi, Kazuma Ohyashiki
• Journal: International journal of hematology (Int J Hematol) Vol. 83 Issue 4 Pg. 294-300 (May 2006) ISSN: 0925-5710 [Print] Japan
• PMID: 16757427 (Publication Type: Journal Article, Review)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Protein-Tyrosine Kinases
• Fusion Proteins, bcr-abl

Topics

• Allosteric Regulation (drug effects, genetics)
• Antineoplastic Agents (chemistry, therapeutic use)
• Binding Sites (drug effects, genetics)
• Drug Design
• Drug Resistance, Neoplasm (drug effects, genetics)
• Fusion Proteins, bcr-abl
• Gene Amplification (drug effects)
• Gene Expression Regulation, Leukemic (drug effects)
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, enzymology, genetics)
• Mutation
• Philadelphia Chromosome
• Protein Binding (drug effects, genetics)
• Protein Kinase Inhibitors (chemistry, therapeutic use)
• Protein Structure, Tertiary (drug effects)
• Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)