Design, synthesis, biological evaluation and molecular modeling of novel 2-amino-4-(1-phenylethoxy) pyridine derivatives as potential ROS1 inhibitors.
Design, synthesis, biological evaluation and molecular modeling of novel 2-amino-4-(1-phenylethoxy) pyridine derivatives as potential ROS1 inhibitors.
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DOI：
10.1016/j.ejmech.2017.11.002
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发表时间：
2018
影响因子：
6.7
通讯作者：
Yuan-xin Tian;Tingting Zhang;Lifan Long;Zhonghuang Li;Shanhe Wan;Guangfa Wang;Yonghuan Yu;J. Hou-J.
中科院分区：
文献类型：
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作者：
Yuan-xin Tian;Tingting Zhang;Lifan Long;Zhonghuang Li;Shanhe Wan;Guangfa Wang;Yonghuan Yu;J. Hou-J.
为了发现潜在的、选择性的ROS1激酶抑制剂，我们合理设计、合成并评价了两个系列的C-3和C-4位带有1-苯基乙氧基的新型2-氨基吡啶衍生物。酶测定结果表明，六种新化合物13b-13d和14a-14c对ROS1激酶表现出明显更高的抑制活性。最有前途的化合物 13d 和 14c 显示出最理想的 ROS1 抑制活性，IC50 值分别为 440 nM 和 370 nM。此外，相对于在激酶结构域中具有约49％氨基酸序列同源性的ALK，13d和14c表现出约7倍和12倍的ROS1抑制选择性。它们还对 ROS1 成瘾的 HCC78 细胞系表现出良好的抗增殖作用，IC50 值分别为 8.1 μM 和 65.3 μM。此外，分子对接和分子动力学模拟研究表明，除了ROS1的选择性结合位点外，化合物14can和13d与Crizotinib具有相似的结合姿势。它还对其活性和选择性给出了可能的分子解释，其中苯环中的甲氧基对于 ROS1 相对于 ALK 的选择性至关重要。
With the aim of discovering potential and selective inhibitors targeting ROS1 kinase, we rationally designed, synthesized and evaluated two series of novel 2-amino-pyridine derivatives with 1-phenylethoxy at C-3 and C-4 position. The enzymic assays results indicated that six of the new compounds13b-13dand14a-14cshowed remarkably higher inhibitory activities against ROS1 kinase. The most promising compounds,13dand14cdisplayed the most desired ROS1 inhibitory activity with IC50values of 440 nM and 370 nM respectively. Furthermore,13dand14cdisplayed ROS1 inhibitory selectivity of about 7-fold and 12-fold, relative to that of ALK sharing about 49% amino acid sequence homology in the kinase domains. They also showed good anti-proliferative effects against ROS1-addicted HCC78 cell lines with the IC50values of 8.1 μM and 65.3 μM, respectively. Moreover, molecular docking and molecular dynamics simulation studies disclosed that compound14cand13dshared similar binding poses with Crizotinib except the selective binding site of ROS1. It also gave a probable molecular explanation for their activity and selectivity, which the methoxyl group in benzene ring was the crucial to the selectivity to ROS1 versus ALK.