新型双重靶向 EGFR 和 ALK 激酶抑制剂的设计、合成及其诱导非小细胞肺癌细胞凋亡。

Novel Dual-Target Kinase Inhibitors of EGFR and ALK Were Designed, Synthesized, and Induced Cell Apoptosis in Non-Small Cell Lung Cancer.

机构信息

School of Pharmacy, Binzhou Medical University, Yantai 264003, China.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

出版信息

Molecules. 2023 Feb 21;28(5):2006. doi: 10.3390/molecules28052006.

ALK-positive NSCLC coexisting with EGFR mutations is a frequently occurring clinical phenomenon. Targeting ALK and EGFR simultaneously may be an effective way to treat these cancer patients. In this study, we designed and synthesized ten new dual-target EGFR/ALK inhibitors. Among them, the optimal compound exhibited good activity with IC values of 0.07829 ± 0.03 μM and 0.08183 ± 0.02 μM against H1975 (EGFR ) and H2228 (EML4-ALK) cells, respectively. Immunofluorescence assays indicated that the compound could simultaneously inhibit the expression of phosphorylated EGFR and ALK proteins. A kinase assay demonstrated that compound could inhibit both EGFR and ALK kinases; thus, exerting an antitumor effect. Additionally, compound induced apoptosis in a dose-dependent manner and inhibited the invasion and migration of tumor cells. All of these results indicate that is worthy of further study.

ALK 阳性 NSCLC 合并 EGFR 突变是一种常见的临床现象。同时针对 ALK 和 EGFR 可能是治疗这些癌症患者的有效方法。在这项研究中，我们设计并合成了十个新的双靶 EGFR/ALK 抑制剂。其中，最优化合物对 H1975（EGFR）和 H2228（EML4-ALK）细胞的 IC 值分别为 0.07829 ± 0.03 μM 和 0.08183 ± 0.02 μM，显示出良好的活性。免疫荧光分析表明，该化合物能够同时抑制磷酸化 EGFR 和 ALK 蛋白的表达。激酶测定表明，化合物能够抑制 EGFR 和 ALK 激酶；从而发挥抗肿瘤作用。此外，化合物呈剂量依赖性诱导细胞凋亡，并抑制肿瘤细胞的侵袭和迁移。所有这些结果表明，化合物值得进一步研究。