化学
喹唑啉
表皮生长因子受体抑制剂
奥西默替尼
吉非替尼
细胞培养
蛋白激酶B
表皮样癌
对接(动物)
表皮生长因子受体
立体化学
生物化学
药理学
埃罗替尼
磷酸化
癌症
受体
生物
遗传学
医学
护理部
作者
Bin Zhang,Zhikun Liu,Shengjin Xia,Qingqing Liu,Shaohua Gou
标识
DOI:10.1016/j.ejmech.2021.113300
摘要
Multi-target, especially dual-target, drug design has become a popular research field for cancer treatment. Development of small molecule dual-target inhibitors through hybridization strategy can provide highly potent and selective anticancer agents. In this study, three series of quinazoline derivatives bearing a benzene-sulfonamide moiety were designed and synthesized as dual EGFR/CAIX inhibitors. All the synthesized compounds were evaluated against epidermoid carcinoma (A431) and non-small cell lung cancer (A549 and H1975) cell lines, which displayed weak to potent anticancer activity. In particular, compound 8v emerged as the most potent derivative against mutant-type H1975 cells, which exhibited comparable activity to osimertinib. Importantly, 8v exhibited stronger anti-proliferative activity than osimertinib against H1975 cells under hypoxic condition. Kinase inhibition studies indicated that 8v showed excellent inhibitory effect on EGFRT790M enzyme, which was 41 times more effective than gefitinib and almost equal to osimertinib. Mechanism studies revealed that 8v exhibited remarkable CAIX inhibitory effect comparable to acetazolamide and significantly inhibited the expression of p-EGFR as well as its downstream p-AKT and p-ERK in H1975 cells. Notably, 8v was found to inhibit the expression of CAIX and its upstream HIF-1α in H1975 cells under hypoxic condition. Molecular docking was also performed to gain insights into the ligand-binding interactions of 8v inside EGFRWT, EGFRT790M and CAIX binding sites.
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