Identification of rocaglate acyl sulfamides as selective inhibitors of glioblastoma stem cells
Date
2024-08-28
Version
Published version
OA Version
Citation
Z. Wang, R.P. Thakare, S. Chitale, A.K. Mishra, S.I. Goldstein, A.C. Fan, R. Li, L.J. Zhu, L.E. Brown, R. Cencic, S. Huang, M.R. Green, J. Pelletier, S.K. Malonia, J.A. Porco. 2024. "Identification of Rocaglate Acyl Sulfamides as Selective Inhibitors of Glioblastoma Stem Cells." ACS Central Science, Volume 10, Issue 8, pp.1640-1656. https://doi.org/10.1021/acscentsci.4c01073
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 translation via targeting 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 EC50 values. 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.
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This article is distributed under the terms of the Creative Commons Attribution 4.0 International .