Second generation Spautin-1 analogues targeting EGFR-mutant non-small cell lung cancer cells

Treatment of advanced stage epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is often complicated by the occurrence of acquired resistance, which emphasizes the need for improved treatment options. Based on a previously reported structure-activity relationship (SAR) study of Spautin-1, which resulted in the discovery of 10a, the search for more potent analogues was envisaged through optimization of the amine substituent. Our search led to the discovery of analogue 15b, harbouring the 2-[4-(4-fluoro-phenoxy)-phenyl]ethylamine substituent, among other potent and original analogues, with nanomolar activity towards EGFR-mutant NSCLC cells. Moreover, this compound 15b showed good selectivity for cancer cells over healthy lung epithelial cells and provides additive effects with food and drug administration (FDA) approved EGFR-tyrosine kinase inhibitors (TKIs), as proven by the co-administration of 15b with Afatinib. Altogether, we report promising lead compounds which show the potential to improve current treatment options.