Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR)
Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR)
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DOI：
10.1021/jm400822z
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发表时间：
2013-09-12
影响因子：
7.3
通讯作者：
Waring, Michael J.
中科院分区：
文献类型：
--
作者：
Ward, Richard A.;Anderton, Mark J.;Waring, Michael J.
已经开发出一系列新型小分子抑制剂，以针对表皮生长因子受体（EGFR）酪氨酸激酶的双突变形式，该激酶对吉非替尼和厄洛替尼治疗具有耐药性。我们报道的化合物还显示出比野生型 EGFR 更高的选择性。在分子模型的指导下，该系列经过进化，通过形成共价键靶向 ATP 结合位点中的半胱氨酸残基，并在 EGFR 双突变体形式的细胞模型中表现出高水平的活性。此外，这些化合物对吉非替尼和厄洛替尼针对的激活突变表现出显着的活性，并且抑制这些突变会产生观察到的临床疗效。基于谷胱甘肽 (GSH) 的测定用于测量硫醇对抑制剂系列亲电功能的反应性，从而能够识别其效力的合适反应窗口，并开发反应性定量结构-性质关系 (QSPR) 以支持设计。
A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.