Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells

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.

Biology of IDH mutant cholangiocarcinoma

“…Other reported vulnerabilities in mIDH cancer cells include sensitivity toward inhibition of BCL-2 family proteins in AML cells, attributed to 2HG defects in mitochondria function, [22] to v-src avian sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog kinase inhibitors in iCCA, [153] and mammalian target of rapamycin inhibitors in glioma. [64,154]…”

One-Pot Multicomponent Synthesis of Allyl and Alkylamines Using a Catalytic System Composed of Ruthenium Nanoparticles on Copper N-Heterocyclic Carbene-Modified Silica

“…Allylamines and alkylamines are key building blocks for the production of a wide range of pharmaceuticals such as antihistamine and anticancer agents (cinnarizine, flunarizine), antimicrobial agents (naftifine, avil, milverine), calcimimetic agents (sensipar), antidepressants (zimelidine), etc. Allylamines are typically prepared by vinylation of imines, nucleophilic allylic substitution, direct allylic amination, and reductive amination of carbonyl compounds .…”