Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning Province, PR China; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, PR China.
Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning Province, PR China.
Eur J Med Chem. 2020 Jan 15;186:111867. doi: 10.1016/j.ejmech.2019.111867. Epub 2019 Nov 12.
Using the principle of bioisosteric replacement, we present a structure-based design approach to obtain new Axl kinase inhibitors with significant activity at the kinase and cellular levels. Through a stepwise structure-activity relationships exploration, a series of 6,7-disubstituted quinoline derivatives, which contain 1,3,4-oxadiazol acetamide moiety as novel Linker, were ultimately synthesized with Axl as the primary target. Most of them exhibited moderate to excellent activity, with IC values ranging from 0.032 to 1.54 μM against the tested cell lines. Among them, the most promising compound 47e, as an Axl kinase inhibitor (IC = 10 nM), shows remarkable cytotoxicity against A549, HT-29, PC-3, MCF-7, H1975 and MDA-MB-231 cell lines. More importantly, 47e also shows a significant inhibitory effect on EGFR-TKI resistant NSCLC cell lines H1975/gefitinib. Meanwhile, this study provides a novel type of linker for Axl kinase inhibitors, namely 1,3,4-oxadiazol acetamide moiety, which is out of the scope of the "5- atoms role ".
利用生物等排替换原理，我们提出了一种基于结构的设计方法，以获得在激酶和细胞水平具有显著活性的新型 Axl 激酶抑制剂。通过逐步的构效关系探索，最终合成了一系列以 Axl 为主要靶点的 6,7-二取代喹啉衍生物，其中包含 1,3,4-噁二唑乙酰胺作为新型连接子。它们中的大多数都表现出中等至优异的活性，对测试细胞系的 IC 值范围为 0.032 至 1.54 μM。其中，最有前途的化合物 47e 作为 Axl 激酶抑制剂（IC = 10 nM），对 A549、HT-29、PC-3、MCF-7、H1975 和 MDA-MB-231 细胞系表现出显著的细胞毒性。更重要的是，47e 对 EGFR-TKI 耐药的 NSCLC 细胞系 H1975/gefitinib 也表现出显著的抑制作用。同时，本研究为 Axl 激酶抑制剂提供了一种新型的连接子，即 1,3,4-噁二唑乙酰胺，它超出了“5 个原子作用”的范围。
