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Recent Developments in the Third Generation Inhibitors of Bcr-Abl for Overriding T315I Mutation

[ Vol. 18 , Issue. 14 ]


X. Y. Lu, Q. Cai and K. Ding   Pages 2146 - 2157 ( 12 )


In the treatment of chronic myeloid leukemia (CML) with Bcr-Abl kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents, such as imatinib, nilotinib and dasatinib, by discrupting important contact interactions between the inhibitors and the enzyme. To overcome this particular resistance, several different strategies have been explored and many molecules have been investigated as capable of potently inhibiting Bcr-Abl T315I. Herein, this review reports on some predominant examples of third generation inhibitors of Bcr-Abl active against the T315I mutation, and special attentions are paid to the “hybrid-design” strategy for creating type-II class ATP-competitive inhibitors.


Bcr-Abl,T315I mutation,Chronic myeloid leukemia,Third generation inhibitors,Tyrosine kinase,DFG in/out,Resistance,Hybrid-design


, , Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences, No. 190, Kaiyuan Avenue, Science Park, Guangzhou,510530, China.

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