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

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.

• Authors: 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
• Journal: Cell chemical biology (Cell Chem Biol) Vol. 30 Issue 2 Pg. 214-229.e18 (02 16 2023) ISSN: 2451-9448 [Electronic] United States
• PMID: 36758549 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Ltd. All rights reserved.

Chemical References

• lanosterol synthase
• 24,25-epoxycholesterol
• Lanosterol
• Cholesterol

Topics

• Adult
• Humans
• Lanosterol (pharmacology, metabolism)
• Brain (metabolism)
• Glioma (drug therapy, metabolism)
• Cholesterol
• Glioblastoma (drug therapy)