Non small cell lung cancer (NSCLC) is the most common form of lung cancer, and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are its standard treatment. A bibenzyl compound mainly, erianin, derived from Dendrobium, which can directly bind to the colchicine site of β-tubulin, inhibit tubulin polymerization, and induce intracellular ferroptosis. However, the accelerated metabolic clearance and acquired drug resistance of erianin result in inadequate therapeutic availability, and structural modification is urgently needed to achieve better therapeutic effects. Studies have shown that the drug resistance of microtubule-targeting agents (MTAs) is notably correlated with the overactivation of the EGFR signaling pathway in NSCLC. Moreover, the combination therapy of MTAs and other anti-tumor drugs represented by EGFR inhibitors has also achieved remarkable success in preclinical and clinical studies. In this research, a series of erianin derivatives as EGFR/tubulin dual-target inhibitors were designed and synthesized based on the structures of the known EGFR inhibitors and erianin. The optimal compound was identified through screening based on cytotoxic activity. Further studies revealed that it can induce ferroptosis by activating autophagy, demonstrating excellent antitumor activity and tumor metastasis inhibition both in vitro and in vivo. This research is expected to provide the new candidate drugs for the treatment of NSCLC through the design of erianin derivatives.
