{"database":"MassIVE","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://massive-ftp.ucsd.edu/v05/MSV000091046/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":{"citationCount":0,"reanalysisCount":0,"viewCount":0,"searchCount":0},"additional":{"omics_type":["Proteomics"],"submitter":["Deepak Nijhawan"],"instrument_platform":["Orbitrap Fusion Lumos"],"species":["Mus Musculus (ncbitaxon:10090)"],"full_dataset_link":["https://massive.ucsd.edu/ProteoSAFe/dataset.jsp?task=7a110ef700464825813aab92d9547032"],"submitter_email":["Deepak.nijhawan@utsouthwestern.edu"],"submitter_affiliation":["University of Texas Southwestern Medical Center"],"sample_protocol":[""],"repository":["MassIVE"],"file_size":["9"],"ptm_modification":["MS:1002864 - No post-translational-modifications are included in the identified peptides of this dataset"],"data_protocol":[""],"pubmed_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."],"pubmed_title":["Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by inducing 24(S),25-epoxycholesterol production."],"pubmed_authors":["Nguyen Thu P TP, Wang Wentian W, Sternisha Alex C AC, Corley Chase D CD, Wang Hua-Yu Leo HL, Wang Xiaoyu X, Ortiz Francisco F, Lim Sang-Kyun SK, Abdullah Kalil G KG, Parada Luis F LF, Williams Noelle S NS, McBrayer Samuel K SK, McDonald Jeffrey G JG, De Brabander Jef K JK, Nijhawan Deepak D"],"name_synonyms":["the brain, Glioma 1, Glioma NOS, 24(S), GLM, glial tumors, 3-oxidosqualene-lanosterol cyclase, neuroglial tumor, secondary metabolites, Mixed Glioma, stalk, Neuroglial Tumor, tumour of the neuroglia, Tumor, Malignant, primary metabolites, [M]Glioma NOS (morphologic abnormality), tumor of the neuroglia, HYPT14 protein, 2, Scanning Transmission Electron Microscopy, [M]Gliomas (morphologic abnormality), synganglion, oxidosqualene cyclase, (3 alpha, primary stem, Mixed Gliomas, 3-oxidosqualene lanosterol cyclase, 24, OSC protein, glioma (morphologic abnormality), Glioma NOS (morphologic abnormality), neuroglial tumour, inhibiteur, Neoplasm of the Neuroglia, cholestan-3-ol, Glial Neoplasm, suprasegmental levels of nervous system, culm, neuroglial neoplasm, 25-epoxy-, glial tumor, inhibidor, tumour of neuroglia, Gliomas (morphologic abnormality), 3-epoxysqualene lanosterol synthase, [M]Gliomas, oxido-squalene cyclase, glioma, Tumors of Neuroglia, neoplasm of the neuroglia, Tumors, inhibitors, Glioma (except Nasal glioma, suprasegmental structures, axis, malignant, LSS protein, inhibitor, obsolete_glioma, Malignant Glioma, 25-epoxycholesterol, Scanning Transmission, encephalon, Cell, neoplasm of neuroglia, Electron Microscopy, CTRCT44 protein, Gliomas, Mixed, Glial Cell Tumor, [M]Glioma NOS, APMR4 protein, antagonists, Glial Tumor, NOS (except Nasal glioma, Neuroglial Neoplasm, Neuroglial Neoplasms, Encephalon, Glial Cell, Malignant glioma, metabolite, Tumor of Neuroglia, human, tumor of neuroglia, Neoplasm of Neuroglia, no ICD-O subtype, antagonists and inhibitors, primary axis, Tumor of the Neuroglia, metabolites, glial tumour, Glial Cell Tumors, STEM, not neoplastic), Malignant Gliomas, 5 beta)-., Glioma, glial neoplasm, malignant (morphologic abnormality), Neoplasms of Neuroglia"],"description_synonyms":["Protein Gene Products, Gene Proteins, protein polypeptide chains, Ro-48-8071, native protein, natural protein, polypeptide chain, (4'-(6-allylmethylaminohexyloxy)-2'-fluorophenyl)-4-(4-bromophenyl)methanone fumarate, protein complex, Protein, Gene Products, Proteins, Gene, proteins, protein, protein aggregate, Acetylenes, protein-containing complex, Ro 48-8071hydrochloride., Acetylenic Compounds, Alkyne"],"pubmed_title_synonyms":["the brain, Glioma 1, Glioma NOS, Policies, 24(S), GLM, glial tumors, 3-oxidosqualene-lanosterol cyclase, neuroglial tumor, Utility, Mixed Glioma, stalk, Neuroglial Tumor, tumour of the neuroglia, Tumor, Malignant, Easterlin, [M]Glioma NOS (morphologic abnormality), tumor of the neuroglia, HYPT14 protein, 2, Scanning Transmission Electron Microscopy, [M]Gliomas (morphologic abnormality), synganglion, oxidosqualene cyclase, (3 alpha, primary stem, 5 beta)-, Mixed Gliomas, Microeconomic, 3-oxidosqualene lanosterol cyclase, 24, OSC protein, Theory, Utility Theories, glioma (morphologic abnormality), Glioma NOS (morphologic abnormality), Household Consumption, neuroglial tumour, Economic Policies, inhibiteur, Neoplasm of the Neuroglia, Microeconomic Factors, cholestan-3-ol, Glial Neoplasm, Living Costs, suprasegmental levels of nervous system, Economic Conditions, culm, neuroglial neoplasm, 25-epoxy-, glial tumor, inhibidor, Capital, tumour of neuroglia, Gliomas (morphologic abnormality), Household Consumptions, 3-epoxysqualene lanosterol synthase, Economic, [M]Gliomas, Theories, oxido-squalene cyclase, glioma, Tumors of Neuroglia, neoplasm of the neuroglia, Tumors, Policy, inhibitors, Economic Policy, Glioma (except Nasal glioma, suprasegmental structures, Home Economics, Indices, Index, axis, malignant, Conditions, Hypothesis, LSS protein, inhibitor, obsolete_glioma, Malignant Glioma, 25-epoxycholesterol, Scanning Transmission, Factor, Production, Living Cost, encephalon, Cell, neoplasm of neuroglia, Macroeconomic Factors, Consumption, Economics, Electron Microscopy, Economic Condition, Household, Consumer Price Index, CTRCT44 protein, Consumer Price, Utility Theory, Macroeconomic, Gliomas, Mixed, Glial Cell Tumor, [M]Glioma NOS, APMR4 protein, antagonists, Glial Tumor, NOS (except Nasal glioma, Factors, Neuroglial Neoplasm, Neuroglial Neoplasms, Encephalon, Remittances., Glial Cell, Consumer Price Indices, Malignant glioma, Tumor of Neuroglia, human, Home, tumor of neuroglia, Condition, Neoplasm of Neuroglia, no ICD-O subtype, Easterlin Hypothesis, Remittance, antagonists and inhibitors, primary axis, Tumor of the Neuroglia, Cost of Living, glial tumour, Glial Cell Tumors, STEM, not neoplastic), Malignant Gliomas, Glioma, glial neoplasm, malignant (morphologic abnormality), Neoplasms of Neuroglia"],"pubmed_abstract_synonyms":["Glioma 1, 24(S), Product, Activity, GLM, Laboratory, glial tumors, 3-oxidosqualene-lanosterol cyclase, postnatal development, Mus domesticus, Pod-1, Mixed Glioma, growth and development, Progress Reports, tumour of the neuroglia, Tumor, ZRS, Astrocytomas, House Mouse, of Leigh, mirror hands and feet with nasal defects, a sterol, [M]Glioma NOS (morphologic abnormality), Summary Report, Leigh syndrome due to mitochondrial Complex 5 deficiency, Pharmaceutical Product, tumor of the neuroglia, 17alpha)-cholest-5-en-3-ol, 2, Scanning Transmission Electron Microscopy, [M]Gliomas (morphologic abnormality), synganglion, 5 beta)-, primary stem, Microeconomic, 14beta, Summary Reports, multicellular organismal biosynthetic process, treatment, average, 24, single-organism biosynthetic process, (3beta, Theory, Utility Theories, laurin Sandrow syndrome, Man (Taxonomy), glioma (morphologic abnormality), enzymes, Progress Report, PPD2, Household Consumption, anabolism, neuroglial tumour, bHLHa23, Economic Policies, Cholest-5-en-3beta-ol, Neoplasm of the Neuroglia, Swiss Mice, cholestan-3-ol, Living Costs, Giant Cell Glioblastoma, suprasegmental levels of nervous system, Astrocytoma, Epicholesterol, 25-epoxy-, Progress, mirror-Image polydactyly, segmental, Field Reports, medicine, Pharmaceutical, grade IV adult Astrocytic tumor, disease management, tumour of neuroglia, Therapies, Gliomas (morphologic abnormality), Household Consumptions, Economic, Malignancies, with absence of tibia and radius, Leigh's necrotizing encephalopathy, house mouse, Theories, glioma, neoplasm of the neuroglia, Tumors, Therapy, Glioma (except Nasal glioma, suprasegmental structures, Home Economics, Indices, Pod1, Index, Hypothesis, Modern, LSS protein, mouse, obsolete_glioma, 25-epoxycholesterol, Malignant Glioma, Giant Cell, brain structure, Macroeconomic Factors, Economics, Electron Microscopy, Economic Condition, capsulin, Household, Benign, batch, Investigative Report, Utility Theory, primary glioblastoma multiforme, THYP, Pharmaceutic, ACHP, Macroeconomic, Gliomas, Glial Cell Tumor, APMR4 protein, epicardin, Mus musculus, Glioblastoma, Factors, growth pattern, spongioblastoma multiforme, non-developmental growth, mice, Encephalon, Consumer Price Indices, Swiss Mouse, Field, GBM, Benign Neoplasms, Tumor of Neuroglia, Treatments, human, Home, OSC, domesticus, Malignant Neoplasms, Condition, subacute necrotizing encephalopathy, Report, Grade IV Astrocytomas, Easterlin Hypothesis, primary axis, Tumor of the Neuroglia, glial tumour, STEM, Biocatalyst, not neoplastic), fibula ulna duplication tibia radius absence, spongioblastoma multiforme., Mouse, Glioma, glial neoplasm, malignant (morphologic abnormality), EPC, Neoplasms of Neuroglia, humans, Remittances, the brain, Brain, Glioma NOS, Policies, human being, Biocatalysts, Neoplasms, fibula and ulna, neuroglial tumor, Benign Neoplasm, Utility, stalk, Neuroglial Tumor, biosynthesis, Grade IV, epc, Malignant, Leigh syndrome due to mitochondrial Complex 2 deficiency, Human, Easterlin, tetramelic mirror-Image polydactyly, Investigative, Homo sapiens, Cholest-5-en-3-ol (3beta)-, House, HYPT14 protein, Mus musculus domesticus, glioblastoma, adult brain, oxidosqualene cyclase, (3 alpha, Giant Cell Glioblastomas, Mice, Mixed Gliomas, 3-oxidosqualene lanosterol cyclase, Man, subacute necrotizing encephalomyelopathy, Drugs, Nervous System, OSC protein, grade IV adult astrocytic tumor, Glioma NOS (morphologic abnormality), Malignancy, SNE, formation, Swiss, Leigh syndrome due to mitochondrial Complex 3 deficiency, inhibiteur, Microeconomic Factors, Glial Neoplasm, TPT, Economic Conditions, culm, neuroglial neoplasm, synthesis, Neoplasias, Glioblastoma Multiforme, drugs, Enzyme, glial tumor, inhibidor, Capital, Leigh syndrome due to mitochondrial Complex 1 deficiency, 3-epoxysqualene lanosterol synthase, Grade IV Astrocytoma, Preparation, [M]Gliomas, oxido-squalene cyclase, Investigative Reports, Tumors of Neuroglia, Pharmaceuticals, Sterol, Cancer, Policy, Economic Policy, inhibitors, Products, grade IV adult astrocytic tumour, neuraxis, Malignant Neoplasm, C7orf2, axis, synthesize, malignant, Conditions, inhibitor, enzyme activity, Scanning Transmission, Factor, Production, Medications, Living Cost, encephalon, Cell, neoplasm of neuroglia, Duplication of, Consumption, development, adult glioblastoma multiforme, DIF14, Consumer Price Index, CTRCT44 protein, Mus, Consumer Price, LSS, cerebrospinal axis, Research Reports, Neoplasm, laurin-Sandrow syndrome, Mixed, Cholesterin, [M]Glioma NOS, Leigh syndrome due to mitochondrial Complex 4 deficiency, glioblastoma multiforme, Glial Tumor, necrotizing encephalopathy, NOS (except Nasal glioma, Neuroglial Neoplasm, Pharmaceutic Preparations, Neuroglial Neoplasms, Glial Cell, postnatal growth, Malignant glioma, Glioblastomas, infantile Subacute, House Mice, Cancers, Laboratory Mice, Drug, tumor of neuroglia, Neoplasm of Neuroglia, Preparations, no ICD-O subtype, Remittance, Therapeutic, Reports, Modern Man, Cost of Living, Glial Cell Tumors, Malignant Gliomas, Treatment, 3-hydroxysteroids, Pharmaceutical Products, Summary, growth, General activity, Laboratory Mouse, Neoplasia, Field Report, Pharmaceutical Preparation"],"citation_count":["0"],"additional_accession":[]},"is_claimable":false,"name":"Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by activating a shunt pathway that generates the toxic metabolite 24(S),25-epoxycholesterol","description":"LUM2_708738 - MM0299-probe bound protein; LUM2_708739 - MM0299 competition; LUM2_850369 - Ro-alkyne bound protein;  LUM2_850370 - Ro 48-8071 competition","dates":{"publication":"Wed Jan 11 10:24:00 GMT 2023"},"accession":"MSV000091046","cross_references":{"pubmed":["36758549"]}}