Assessment of Rocaglates and Targeted Derivatives as Selective Inhibitors of Glioblastoma Stem Cells

A substantial body of evidence suggests that the initiation, progression, and recurrence of glioblastomas (GBM) are driven by a small subpopulation (1-5%) of cells within the tumor known as tumor-initiating cells or cancer stem cells (CSCs). GBM CSCs play a pivotal role in orchestrating drug resistance mechanisms and tumor relapse. As a prospective avenue for GBM intervention, targeted suppression of GBM CSCs holds promise. In this study, we identified novel rocaglate derivatives (rocaglate acyl sulfamides (Roc ASFs)) that can inhibit GBM CSCs with nanomolar (nM) EC50s. Our findings, supported by comparative dose-response assays and functional characterizations, demonstrate that these derivatives exert a robust, dose-dependent cytotoxic impact on GBM CSCs. Furthermore, our investigations into target identification have unveiled the DEAD box helicase DDX3X as a specific target of Roc ASFs. Inhibiting DDX3X using Roc ASF derivatives confers selective cytotoxicity to GBM CSCs. These findings suggest a promising therapeutic strategy for targeting GBM CSCs.