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

doi:10.1016/j.chembiol.2023.01.005

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 journal › Article › peer-review

1 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 language	English (US)
Pages (from-to)	214-229.e18
Journal	Cell Chemical Biology
Volume	30
Issue number	2
DOIs	https://doi.org/10.1016/j.chembiol.2023.01.005
State	Published - 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

Access to Document

10.1016/j.chembiol.2023.01.005

Cite this

Nguyen, T. P., Wang, W., Sternisha, A. C., Corley, C. D., Wang, H. Y. L., Wang, X., Ortiz, F., Lim, S. K., Abdullah, K. G., Parada, L. F., Williams, N. S., McBrayer, S. K., McDonald, J. G., De Brabander, J. K., & Nijhawan, D. (2023). Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by inducing 24(S),25-epoxycholesterol production. Cell Chemical Biology, 30(2), 214-229.e18. https://doi.org/10.1016/j.chembiol.2023.01.005

Nguyen, TP, Wang, W, Sternisha, AC, Corley, CD, Wang, HYL, Wang, X, Ortiz, F, Lim, SK, Abdullah, KG, Parada, LF, Williams, NS , McBrayer, SK , McDonald, JG , De Brabander, JK & Nijhawan, D 2023, 'Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by inducing 24(S),25-epoxycholesterol production', Cell Chemical Biology, vol. 30, no. 2, pp. 214-229.e18. https://doi.org/10.1016/j.chembiol.2023.01.005

@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 = "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 = "2451-9456",

publisher = "Elsevier Inc.",

number = "2",

}

TY - JOUR

T1 - Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by inducing 24(S),25-epoxycholesterol production

AU - Nguyen, Thu P.

AU - Wang, Wentian

AU - Sternisha, Alex C.

AU - Corley, Chase D.

AU - Wang, Hua Yu Leo

AU - Wang, Xiaoyu

AU - Ortiz, Francisco

AU - Lim, Sang Kyun

AU - Abdullah, Kalil G.

AU - Parada, Luis F.

AU - Williams, Noelle S.

AU - McBrayer, Samuel K.

AU - McDonald, Jeffrey G.

AU - De Brabander, Jef K.

AU - Nijhawan, Deepak

PY - 2023/2/16

Y1 - 2023/2/16

N2 - 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.

AB - 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.

KW - LSS

KW - epoxycholesterol

KW - glioblastoma

KW - lanosterol synthase inhibitors

KW - shunt pathway

UR - http://www.scopus.com/inward/record.url?scp=85147980333&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85147980333&partnerID=8YFLogxK

U2 - 10.1016/j.chembiol.2023.01.005

DO - 10.1016/j.chembiol.2023.01.005

M3 - Article

C2 - 36758549

AN - SCOPUS:85147980333

SN - 2451-9456

VL - 30

SP - 214-229.e18

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 2

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this