SGX393 inhibits the CML mutant Bcr-AblT3151 and preempts in vitro resistance when combined with nilotinib or dasatinib
SGX393 inhibits the CML mutant Bcr-AblT3151 and preempts in vitro resistance when combined with nilotinib or dasatinib
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DOI：
10.1073/pnas.0800587105
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发表时间：
2008-04-08
影响因子：
11.1
通讯作者：
Deininger, Michael W.
中科院分区：
文献类型：
--
作者：
O'Hare, Thomas;Eide, Christopher A.;Deininger, Michael W.
Imatinib inhibits Bcr-Abl, the oncogenic tyrosine kinase that causes chronic myeloid leukemia. The second-line inhibitors nilotinib and dasatinib are effective in patients with imatinib resistance resulting from Bcr-Abl kinase domain mutations. Bcr-Abl(T3151), however, is resistant to all Abl kinase inhibitors in clinical use and is emerging as the most frequent cause of salvage therapy failure. SGX393 is a potent inhibitor of native and T3151-mutant Bcr-Abl kinase that blocks the growth of leukemia cell lines and primary hematopoietic cells expressing Bcr-Abl(T3151), with minimal toxicity against Bcr-Abl-negative cell lines or normal bone marrow. A screen for Bcr-Abl mutants emerging in the presence of SGX393 revealed concentration-dependent reduction in the number and range of mutations. Combining SGX393 with nilotinib or dasatinib preempted emergence of resistant subclones, including Bcr-Abl(T3151). These findings suggest that combination of a T3151 inhibitor with the current clinically used inhibitors may be useful for reduction of Bcr-Abl mutants in Philadelphia chromosome-positive leukemia.
