Identification of Rocaglate Acyl Sulfamides as Selective Inhibitors of Glioblastoma Stem Cells.

in ACS central science by Zihao Wang, Ritesh P Thakare, Shalaka Chitale, Alok K Mishra, Stanley I Goldstein, Alice C Fan, Rui Li, Lihua Julie Zhu, Lauren E Brown, Regina Cencic, Sidong Huang, Michael R Green, Jerry Pelletier, Sunil K Malonia, John A Porco

TLDR

  • The study found that rocaglates, compounds that inhibit translation targeting of the DEAD-box helicase eIF4A, can kill GBM CSCs, which are the bad cells that cause brain tumors. The study also found that rocaglates can selectively kill GBM CSCs and not the good cells in the brain. The study also found that rocaglates can target a specific protein called DDX3X, which is important for the bad cells to survive. The study's findings suggest that rocaglates could be used as a treatment for brain tumors.

Abstract

Glioblastoma (GBM) is the most aggressive and frequently occurring type of malignant brain tumor in adults. The initiation, progression, and recurrence of malignant tumors are known to be driven by a small subpopulation of cells known as tumor-initiating cells or cancer stem cells (CSCs). GBM CSCs play a pivotal role in orchestrating drug resistance and tumor relapse. As a prospective avenue for GBM intervention, the targeted suppression of GBM CSCs holds considerable promise. In this study, we found that rocaglates, compounds which are known to inhibit translationtargeting of the DEAD-box helicase eIF4A, exert a robust, dose-dependent cytotoxic impact on GBM CSCs with minimal killing of nonstem GBM cells. Subsequent optimization identified novel rocaglate derivatives (rocaglate acyl sulfamides or Roc ASFs) that selectively inhibit GBM CSCs with nanomolar ECvalues. Furthermore, comparative evaluation of a lead CSC-optimized Roc ASF across diverse mechanistic and target profiling assays revealed suppressed translation inhibition relative to that of other CSC-selective rocaglates, with enhanced targeting of the DEAD-box helicase DDX3X, a recently identified secondary target of rocaglates. Overall, these findings suggest a promising therapeutic strategy for targeting GBM CSCs.

Overview

  • The study investigates the potential of rocaglates, compounds that inhibit translation targeting of the DEAD-box helicase eIF4A, as a therapeutic strategy for targeting GBM CSCs. The study aims to identify novel rocaglate derivatives with selective cytotoxicity against GBM CSCs and evaluate their targeting of DEAD-box helicases. The study uses a combination of in vitro and in vivo assays to evaluate the efficacy of rocaglates and their derivatives against GBM CSCs and nonstem GBM cells. The study also uses mechanistic and target profiling assays to evaluate the targeting of DEAD-box helicases by rocaglates and their derivatives.

Comparative Analysis & Findings

  • The study found that rocaglates exert a robust, dose-dependent cytotoxic impact on GBM CSCs with minimal killing of nonstem GBM cells. Subsequent optimization identified novel rocaglate derivatives (rocaglate acyl sulfamides or Roc ASFs) that selectively inhibit GBM CSCs with nanomolar ECvalues. The study also found that a lead CSC-optimized Roc ASF exhibited suppressed translation inhibition relative to other CSC-selective rocaglates, with enhanced targeting of the DEAD-box helicase DDX3X, a recently identified secondary target of rocaglates.

Implications and Future Directions

  • The study's findings suggest a promising therapeutic strategy for targeting GBM CSCs. The study identifies novel rocaglate derivatives with selective cytotoxicity against GBM CSCs and evaluates their targeting of DEAD-box helicases. The study also identifies a lead CSC-optimized Roc ASF with enhanced targeting of DDX3X, a secondary target of rocaglates. The study's findings suggest that rocaglates and their derivatives could be used as a therapeutic strategy for targeting GBM CSCs. Future research could focus on further optimization of rocaglates and their derivatives, as well as evaluation of their efficacy in preclinical and clinical studies.
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