Targeting EGFR/HER2 tyrosine kinases with a new potent series of 6-substituted 4-anilinoquinazoline hybrids: Design, synthesis, kinase assay, cell-based assay, and molecular docking
Targeting EGFR/HER2 tyrosine kinases with a new potent series of 6-substituted 4-anilinoquinazoline hybrids: Design, synthesis, kinase assay, cell-based assay, and molecular docking
复制标题
DOI：
10.1016/j.bmcl.2015.10.003
复制
发表时间：
2015-11-15
影响因子：
2.7
通讯作者：
Roh, Eun Joo
中科院分区：
文献类型：
--
作者：
Elkamhawy, Ahmed;Farag, Ahmed Karam;Roh, Eun Joo
EGFR和HER2在乳腺癌、卵巢癌、结肠癌、前列腺癌等多种肿瘤中均有共表达，患者预后较差。本研究团队设计合成了18种以6-取代4-苯胺喹啉为核心的选择性抑制EGFR/HER2酪氨酸激酶的新化合物。12种化合物（8a-8d、9a、9c、9d、10a、10c、11b、14和15）对EGFR和/或HER2激酶的IC50值在纳摩尔范围内。据此，建立了详细的结构活度关系（SAR）。分子对接研究证实了8d、9b、9d和10d在两种激酶ATP活性位点的良好结合模式。对化合物8d进行的激酶选择性分析显示，化合物8d对EGFR和HER2具有很高的选择性。8d、9c和9d对BT-474细胞株具有选择性的细胞毒活性，IC50值分别为2.70、1.82和1.95 μ M。根据这些结果，我们报告类似物8d， 9c和9d作为有希望的候选人，在激酶抑制效力和抗增殖活性方面发现了平衡良好的化合物。(C) 2015 Elsevier Ltd.版权所有。
Coexpression of EGFR and HER2 has been found in many tumors such as breast, ovarian, colon and prostate cancers, with poor prognosis of the patients. Herein, our team has designed and synthesized new eighteen compounds with 6-substituted 4-anilinoquinazoline core to selectively inhibit EGFR/HER2 tyrosine kinases. Twelve compounds (8a-8d, 9a, 9c, 9d, 10a, 10c, 11b, 14, and 15) showed nanomolar range of IC50 values on EGFR and/or HER2 kinases. Accordingly, a detailed structure activity relationship (SAR) was established. A molecular docking study demonstrated the favorable binding modes of 8d, 9b, 9d and 10d at the ATP active site of both kinases. A kinase selectivity profile performed for compound 8d showed great selectivity for EGFR and HER2. In addition, 8d, 9c, and 9d exerted selective promising cytotoxic activity over BT-474 cell line with IC50 values of 2.70, 1.82 and 1.95 mu M, respectively. From these results, we report analogs 8d, 9c, and 9d as promising candidates for the discovery of well-balanced compounds in terms of the kinase inhibitory potency and antiproliferative activity. (C) 2015 Elsevier Ltd. All rights reserved.