EGFR and ALK are common driver genes in NSCLC, and more patients with these mutations are being identified due to medical advances. Thus, developing dual-target EGFR/ALK inhibitors is crucial. In this study, 10 novel small molecules were designed and synthesized. CCK8 experiments revealed that compound (−)-9a exhibited the best anti-tumor activity, with IC50 values of 1.08 ± 0.07 nM for EGFR and 2.395 ± 0.023 nM for ALK mutant tumor cells. Studies show that compound (−)-9a can inhibit phosphorylated proteins in EGFR, ALK, and BRK signaling pathways and halt the cell cycle, leading to reduced mitochondrial membrane potential and apoptosis in tumor cells. Additionally, (−)-9a not only directly targets tumor cells but also exhibits potential immune-enhancing effects. Furthermore, evaluations conducted in animal models have demonstrated that this drug effectively reduces tumor growth in vivo. In summary, (−)-9a boasts dual-targeting, potent antitumor activity, and immune-enhancing potential, presenting vast potential as a next-gen anticancer drug.

中文翻译：

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新型氘代 EGFR/ALK 双靶点抑制剂的合成及其对非小细胞肺癌的活性


EGFR 和 ALK 是 NSCLC 中常见的驱动基因，由于医学的进步，越来越多的具有这些突变的患者被识别出来。因此，开发双靶点 EGFR/ALK 抑制剂至关重要。在这项研究中，设计并合成了 10 个新型小分子。CCK8 实验显示，化合物 （-）-9a 表现出最佳的抗肿瘤活性，EGFR 的 IC50 值为 1.08 ± 0.07 nM，ALK 突变肿瘤细胞的 IC50 值为 2.395 ± 0.023 nM。研究表明，化合物 （-）-9a 可以抑制 EGFR、ALK 和 BRK 信号通路中的磷酸化蛋白并停止细胞周期，导致肿瘤细胞线粒体膜电位降低和细胞凋亡。此外，（-）-9a 不仅直接靶向肿瘤细胞，而且还表现出潜在的免疫增强作用。此外，在动物模型中进行的评估表明，这种药物可有效减少体内肿瘤生长。综上所述，（−）-9a 具有双靶向、强效抗肿瘤活性和免疫增强潜力，作为下一代抗癌药物具有巨大潜力。