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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

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

Author(s): X. Y. Lu, Q. Cai and K. Ding

Volume 18, Issue 14, 2011

Page: [2146 - 2157] Pages: 12

DOI: 10.2174/092986711795656135

Price: $65


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.

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

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