Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by inducing 24(S),25-epoxycholesterol production

Thu P. Nguyen, Wentian Wang, Alex C. Sternisha, Chase D. Corley, Hua Yu Leo Wang, Xiaoyu Wang, Francisco Ortiz, Sang Kyun Lim, Kalil G. Abdullah, Luis F. Parada, Noelle S. Williams, Samuel K. McBrayer, Jeffrey G. McDonald, Jef K. De Brabander, Deepak Nijhawan

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Glioblastoma (GBM) is an aggressive adult brain cancer with few treatment options due in part to the challenges of identifying brain-penetrant drugs. Here, we investigated the mechanism of MM0299, a tetracyclic dicarboximide with anti-glioblastoma activity. MM0299 inhibits lanosterol synthase (LSS) and diverts sterol flux away from cholesterol into a “shunt” pathway that culminates in 24(S),25-epoxycholesterol (EPC). EPC synthesis following MM0299 treatment is both necessary and sufficient to block the growth of mouse and human glioma stem-like cells by depleting cellular cholesterol. MM0299 exhibits superior selectivity for LSS over other sterol biosynthetic enzymes. Critical for its application in the brain, we report an MM0299 derivative that is orally bioavailable, brain-penetrant, and induces the production of EPC in orthotopic GBM tumors but not normal mouse brain. These studies have implications for the development of an LSS inhibitor to treat GBM or other neurologic indications.

Original languageEnglish (US)
Pages (from-to)214-229.e18
JournalCell Chemical Biology
Volume30
Issue number2
DOIs
StatePublished - Feb 16 2023

Keywords

  • LSS
  • epoxycholesterol
  • glioblastoma
  • lanosterol synthase inhibitors
  • shunt pathway

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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