@article{a656e166eb2d4d5196e862a64add689f,
title = "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.",
keywords = "LSS, epoxycholesterol, glioblastoma, lanosterol synthase inhibitors, shunt pathway",
author = "Nguyen, {Thu P.} and Wentian Wang and Sternisha, {Alex C.} and Corley, {Chase D.} and Wang, {Hua Yu Leo} and Xiaoyu Wang and Francisco Ortiz and Lim, {Sang Kyun} and Abdullah, {Kalil G.} and Parada, {Luis F.} and Williams, {Noelle S.} and McBrayer, {Samuel K.} and McDonald, {Jeffrey G.} and {De Brabander}, {Jef K.} and Deepak Nijhawan",
note = "Funding Information: We thank Anderson Frank and Joseph Ready for critically evaluating our manuscript and helpful discussion, J. Goldstein for providing human LDL, UTSW Proteomics Core for sample preparation and proteomics mass spectrometry analysis, Katy Lowe for assistance with sterolomics sample preparation, and Jiwoong Kim for assistance with RNA-sequencing data processing. T.P.N. is supported by a McKnight Fellowship . J.G.M. is supported in part by HL020948 and HL160487 . D.N. is a UT Presidential Scholar and holds the Joseph F. Sambrook, Ph.D. Distinguished Chair in Biomedical Science. J.K.D. holds the Julie and Louis Beecherl, Jr., Chair in Medical Science. J.K.D. and D.N. acknowledge support of the Welch Foundation (grants I-1422 and I-1879 ). Funding Information: We thank Anderson Frank and Joseph Ready for critically evaluating our manuscript and helpful discussion, J. Goldstein for providing human LDL, UTSW Proteomics Core for sample preparation and proteomics mass spectrometry analysis, Katy Lowe for assistance with sterolomics sample preparation, and Jiwoong Kim for assistance with RNA-sequencing data processing. T.P.N. is supported by a McKnight Fellowship. J.G.M. is supported in part by HL020948 and HL160487. D.N. is a UT Presidential Scholar and holds the Joseph F. Sambrook, Ph.D. Distinguished Chair in Biomedical Science. J.K.D. holds the Julie and Louis Beecherl, Jr. Chair in Medical Science. J.K.D. and D.N. acknowledge support of the Welch Foundation (grants I-1422 and I-1879). T.P.N. designed and performed MM0299 and Ro 48-8071 target identification, compound toxicity studies, and sterolomics studies, and wrote the manuscript. W.W. synthesized Ro-alkyne and d6-EPL, and developed sterolomics LC-MS methods. H.-Y.L.W. synthesized MM0299 analogs. A.C.S. tested MM0299 efficacy in human GSCs and established orthotopic GBM tumors in mice. C.D.C. performed cellular sterolomics analysis. K.G.A. developed UTSW63 and UTSW71 human GSCs. X.W. and F.O. performed pharmacokinetic, compound stability, and protein binding studies. S.K.L. performed the initial chemical screen on mouse GSCs. L.F.P. designed and supervised the generation of mouse GSCs and the initial chemical screen. N.S.W. designed, performed, and supervised pharmacokinetic, compound stability, and protein binding studies. S.K.M. designed and supervised the generation of human GSCs and compound toxicity studies in these cell lines. J.G.M. designed and supervised sterolomics LC-MS method development, sample preparation, and data analysis. J.K.D.B. designed and supervised chemical synthetic strategies, target identification, and compound toxicity studies, and wrote the manuscript. D.N. designed and supervised target identification, compound toxicity studies and wrote the manuscript. A patent application related to this work has been filed by University of Texas Southwestern Medical Center. Publisher Copyright: {\textcopyright} 2023 Elsevier Ltd",
year = "2023",
month = feb,
day = "16",
doi = "10.1016/j.chembiol.2023.01.005",
language = "English (US)",
volume = "30",
pages = "214--229.e18",
journal = "Cell Chemical Biology",
issn = "2451-9448",
publisher = "Elsevier Inc.",
number = "2",
}