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

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

  • Cell Chem Biol. 2023 Feb 16;30(2):214-229.e18. doi: 10.1016/j.chembiol.2023.01.005.
Thu P Nguyen 1,  Wentian Wang 1,  Alex C Sternisha 2,  Chase D Corley 3,  Hua-Yu Leo Wang 1,  Xiaoyu Wang 1,  Francisco Ortiz 1,  Sang-Kyun Lim 4,  Kalil G Abdullah 5,  Luis F Parada 4,  Noelle S Williams 1,  Samuel K McBrayer 2,  Jeffrey G McDonald 3,  Jef K De Brabander 6,  Deepak Nijhawan 7
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2 Children's Medical Center Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 3 Center for Human Nutrition, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4 Department of Development Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 5 Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • 6 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: jef.debrabander@utsouthwestern.edu.
  • 7 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, Program in Molecular Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: deepak.nijhawan@utsouthwestern.edu.
PMID: 36758549 DOI: 10.1016/j.chembiol.2023.01.005
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.

Keywords

LSS; epoxycholesterol; glioblastoma; lanosterol synthase inhibitors; shunt pathway.

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