Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing, 211189, China; Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing, 211189, China; Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
Eur J Med Chem. 2021 Apr 15;216:113300. doi: 10.1016/j.ejmech.2021.113300. Epub 2021 Feb 20.
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 EGFR 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 EGFR, EGFR and CAIX binding sites.
多靶点，特别是双靶点，药物设计已成为癌症治疗的热门研究领域。通过杂交策略开发小分子双靶点抑制剂可以提供高效和选择性的抗癌剂。在这项研究中，设计并合成了三个系列含有苯磺酰胺部分的喹唑啉衍生物，作为双 EGFR/CAIX 抑制剂。所有合成的化合物都针对表皮样癌细胞（A431）和非小细胞肺癌（A549 和 H1975）细胞系进行了评估，显示出弱至强的抗癌活性。特别是化合物 8v 对突变型 H1975 细胞表现出最强的活性，与奥希替尼相当。重要的是，8v 在低氧条件下对 H1975 细胞的增殖抑制活性强于奥希替尼。激酶抑制研究表明，8v 对 EGFR 酶表现出极好的抑制作用，其抑制效果比吉非替尼强 41 倍，几乎与奥希替尼相当。机制研究表明，8v 对 CAIX 的抑制作用与乙酰唑胺相当，显著抑制了 H1975 细胞中 p-EGFR 及其下游 p-AKT 和 p-ERK 的表达。值得注意的是，在低氧条件下，8v 被发现抑制了 H1975 细胞中 CAIX 和其上游 HIF-1α的表达。还进行了分子对接，以深入了解 8v 在 EGFR、EGFR 和 CAIX 结合位点内的配体结合相互作用。
