Characterization of a conserved structural determinant controlling protein kinase sensitivity to selective inhibitors
Characterization of a conserved structural determinant controlling protein kinase sensitivity to selective inhibitors
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DOI：
10.1016/j.chembiol.2004.02.029
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发表时间：
2004-05-01
影响因子：
--
通讯作者：
Daub, H
中科院分区：
文献类型：
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作者：
Blencke, S;Zech, B;Daub, H
已知一些蛋白激酶在ATP结合位点处的保守苏氨酸突变为较大残基后获得对选择性小分子抑制剂的抗性。在这里，我们进行了全面的突变分析，这种结构元素，并确定了细胞的敏感性，几种疾病相关的酪氨酸激酶对各种抑制剂。在关键位点具有较大侧链的突变激酶显示出对大多数测试化合物的抗性，例如ZD 1839、PP 1、AG 1296、STI 571和吡啶并[2，3-d]嘧啶抑制剂。相比之下，吲哚酮影响野生型和突变体激酶具有相似的效力。建立耐药突变体用于β PDGF受体介导的信号传导的药理学分析，并允许产生细胞Src激酶活性的药物诱导系统。我们的数据建立了一个保守的结构决定蛋白激酶的敏感性相关的信号转导研究和药物开发。
Some protein kinases are known to acquire resistance to selective small molecule inhibitors upon mutation of a conserved threonine at the ATP binding site to a larger residue. Here, we performed a comprehensive mutational analysis of this structural element and determined the cellular sensitivities of several disease-relevant tyrosine kinases against various inhibitors. Mutant kinases possessing a larger side chain at the critical site showed resistance to most compounds tested, such as ZD1839, PP1, AG1296, STI571, and a pyrido[2,3-d]pyrimidine inhibitor. In contrast, indolinones affected both wild-type and mutant kinases with similar potencies. Resistant mutants were established for pharmacological analysis of betaPDGF receptor-mediated signaling and allowed the generation of a drug-inducible system of cellular Src kinase activity. Our data establish a conserved structural determinant of protein kinase sensitivity relevant for both signal transduction research and drug development.