羊毛甾醇
化学
胶质瘤
药理学
渗透剂(生化)
酶
甾醇
癌症研究
生物化学
生物
胆固醇
有机化学
作者
Thu P Nguyen,Wentian Wang,Alex Sternisha,Chase D Corley,Hua-Yu Leo Wang,Xiaoyu Wang,Francisco Ortiz,Sang Kyoo Lim,Kalil G. Abdullah,Luis F. Parada,Noelle S. Williams,Samuel K. McBrayer,Jeffrey G. McDonald,Jef K. De Brabander,Deepak Nijhawan
标识
DOI:10.1016/j.chembiol.2023.01.005
摘要
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.
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