Identification\nof Rocaglate Acyl Sulfamides as Selective\nInhibitors of Glioblastoma Stem Cells

Glioblastoma (GBM) is the most aggressive and frequently\noccurring\ntype of malignant brain tumor in adults. The initiation, progression,\nand recurrence of malignant tumors are known to be driven by a small\nsubpopulation of cells known as tumor-initiating cells or cancer stem\ncells (CSCs). GBM CSCs play a pivotal role in orchestrating drug resistance\nand tumor relapse. As a prospective avenue for GBM intervention, the\ntargeted suppression of GBM CSCs holds considerable promise. In this\nstudy, we found that rocaglates, compounds which are known to inhibit\ntranslation <i>via</i> targeting of the DEAD-box helicase\neIF4A, exert a robust, dose-dependent cytotoxic impact on GBM CSCs\nwith minimal killing of nonstem GBM cells. Subsequent optimization\nidentified novel rocaglate derivatives (rocaglate acyl sulfamides\nor Roc ASFs) that selectively inhibit GBM CSCs with nanomolar EC<sub>50</sub> values. Furthermore, comparative evaluation of a lead CSC-optimized\nRoc ASF across diverse mechanistic and target profiling assays revealed\nsuppressed translation inhibition relative to that of other CSC-selective\nrocaglates, with enhanced targeting of the DEAD-box helicase DDX3X,\na recently identified secondary target of rocaglates. Overall, these\nfindings suggest a promising therapeutic strategy for targeting GBM\nCSCs.