Abl tyrosine kinase inhibitors for overriding Bcr-Abl/T315l: from the second to third generation

作者：Tanaka Ruriko; Kimura Shinya^*

来源：Expert Review of Anticancer Therapy, 2008, 8(9): 1387-1398.

DOI：10.1586/14737140.8.9.1387

• aurora kinase
• bosutinib
• chronic myeloid leukemia
• dasatinib
• farnesyl transferase
• HDAC
• heat-shock protein
• imatinib
• INNO-406
• nilotinib
• T315l

Treatment of chronic myeloid leukemia (CIVIL) has changed drastically with the emergence of the AN tyrosine kinase inhibitor (TKI), imatinib mesylate. However, primary and secondary resistance have frequently been reported, particularly in patients with advanced-stage disease. Point mutations within the Abl kinase domain that interfere with imatinib binding are the most critical cause of imatinib resistance. In order to override this resistance, several second generation ATP-competitive Abl TKIs including dasatinib, nilotinib, bosutinib and INNO-406 have been developed. Despite promising clinical results from these novel Abl TKIs for most mutations, the frequently observed mutant T315l is not effectively targeted by any of these agents. Thus, identification of novel agents and the development of new strategies for the effective treatment of CIVIL patients with the T315l mutation are important and challenging tasks. In this review, the current status of novel agents for CIVIL treatment is overviewed as follows: pathogenesis and features of CIVIL; imatinib and second-generation AN TKIs; why Abl TKIs are not effective against T315l; and novel agents that may override the T315l mutation.

• 出版日期2008-9