Conformation-Selective Analogues of Dasatinib Reveal Insight into Kinase Inhibitor Binding and Selectivity
Conformation-Selective Analogues of Dasatinib Reveal Insight into Kinase Inhibitor Binding and Selectivity
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DOI：
10.1021/acschembio.5b01018
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发表时间：
2016-05-01
影响因子：
4
通讯作者：
Soellner, Matthew B.
中科院分区：
文献类型：
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作者：
Kwarcinski, Frank E.;Brandvold, Kristoffer R.;Soellner, Matthew B.
在激酶领域，关于构象选择性抑制剂有许多广泛持有的原则，但尚未通过对照实验进行验证。我们设计、合成并表征了达沙替尼的一系列激酶抑制剂类似物，达沙替尼是 FDA 批准的与活性构象结合的激酶抑制剂。该抑制剂系列包括两种结合 DFG-out 非活性构象的 II 型抑制剂和两种结合 alpha C-helix-out 非活性构象的抑制剂。使用这一系列化合物，我们分析了构象选择性抑制剂对靶标结合和激酶组选择性的影响。
In the kinase field, there are many widely held tenets about conformation-selective inhibitors that have yet to be validated using controlled experiments. We have designed, synthesized, and characterized a series of kinase inhibitor analogues of dasatinib, an FDA-approved kinase inhibitor that binds the active conformation. This inhibitor series includes two Type II inhibitors that bind the DFG-out inactive conformation and two inhibitors that bind the alpha C-helix-out inactive conformation. Using this series of compounds, we analyze the impact that conformation-selective inhibitors have on target binding and kinome-wide selectivity.