Synthesis of novel deuterated EGFR/ALK dual-target inhibitors and their activity against non-small cell lung cancer.

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 IC 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.