1. Academic Validation
  2. Targeting of REST with rationally-designed small molecule compounds exhibits synergetic therapeutic potential in human glioblastoma cells

Targeting of REST with rationally-designed small molecule compounds exhibits synergetic therapeutic potential in human glioblastoma cells

  • BMC Biol. 2024 Apr 12;22(1):83. doi: 10.1186/s12915-024-01879-0.
Svetlana B Panina 1 Joshua V Schweer 2 Qian Zhang 1 Gaurav Raina 2 Haley A Hardtke 1 Seungjin Kim 1 Wanjie Yang 1 Dionicio Siegel 2 Y Jessie Zhang 3
Affiliations

Affiliations

  • 1 Department of Molecular Biosciences, The University of Texas at Austin, 2500 Speedway, Austin, TX, USA.
  • 2 Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of California San Diego, 9500 Gilman Drive 0741, La Jolla, CA, USA.
  • 3 Department of Molecular Biosciences, The University of Texas at Austin, 2500 Speedway, Austin, TX, USA. jzhang@cm.utexas.edu.
Abstract

Background: Glioblastoma (GBM) is an aggressive brain Cancer associated with poor prognosis, intrinsic heterogeneity, plasticity, and therapy resistance. In some GBMs, cell proliferation is fueled by a transcriptional regulator, repressor element-1 silencing transcription factor (REST).

Results: Using CRISPR/Cas9, we identified GBM cell lines dependent on REST activity. We developed new small molecule inhibitory compounds targeting small C-terminal domain Phosphatase 1 (SCP1) to reduce REST protein level and transcriptional activity in glioblastoma cells. Top leads of the series like GR-28 exhibit potent cytotoxicity, reduce REST protein level, and suppress its transcriptional activity. Upon the loss of REST protein, GBM cells can potentially compensate by rewiring fatty acid metabolism, enabling continued proliferation. Combining REST inhibition with the blockade of this compensatory adaptation using long-chain acyl-CoA synthetase inhibitor Triacsin C demonstrated substantial synergetic potential without inducing hepatotoxicity.

Conclusions: Our results highlight the efficacy and selectivity of targeting REST alone or in combination as a therapeutic strategy to combat high-REST GBM.

Keywords

Glioblastoma (GBM); Repressor element-1 silencing transcription factor; SCP1 phosphatase; Synergy.

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