Novel mtorc1 inhibitors kill glioblastoma stem cells

Jose A. Sandoval, Alexey Tomilov, Sandipan Datta, Sonia Allen, Robert O’Donnell, Thomas Sears, Kevin D Woolard, Dmytro Kovalskyy, James M. Angelastro, Gino Cortopassi

Research output: Contribution to journalArticlepeer-review

Abstract

Glioblastoma (GBM) is an aggressive tumor of the brain, with an average post-diagnosis survival of 15 months. GBM stem cells (GBMSC) resist the standard-of-care therapy, temozolomide, and are considered a major contributor to tumor resistance. Mammalian target of rapamycin Complex 1 (mTORC1) regulates cell proliferation and has been shown by others to have reduced activity in GBMSC. We recently identified a novel chemical series of human-safe piperazine-based brain-penetrant mTORC1-specific inhibitors. We assayed the piperazine-mTOR binding strength by two biophysical measurements, biolayer interferometry and field-effect biosensing, and these confirmed each other and demonstrated a structure–activity relationship. As mTORC1 is altered in human GBMSC, and as mTORC1 inhibitors have been tested in previous GBM clinical trials, we tested the killing potency of the tightest-binding piperazines and observed that these were potent GBMSC killers. GBMSCs are resistant to the standard-of-care temozolomide therapy, but temozolomide supplemented with tight-binding piperazine meclizine and flunarizine greatly enhanced GBMSC death over temozolomide alone. Lastly, we investigated IDH1-mutated GBMSC mutations that are known to affect mitochondrial and mTORC1 metabolism, and the tight-binding meclizine provoked ‘synthetic lethality’ in IDH1-mutant GBMSCs. In other words, IDH1-mutated GBMSC showed greater sensitivity to the coadministration of temozolomide and meclizine. These data tend to support a novel clinical strategy for GBM, i.e., the co-administration of meclizine or flunarizine as adjuvant therapy in the treatment of GBM and IDH1-mutant GBM.

Original languageEnglish (US)
Article number419
Pages (from-to)1-18
Number of pages18
JournalPharmaceuticals
Volume13
Issue number12
DOIs
StatePublished - Dec 2020

Keywords

  • Glioblastoma
  • Meclizine
  • MTOR
  • MTORC1
  • Piperazine

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science

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