Elucidation of the Mechanism of Action of a Cell Line Selective Toxin

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dc.contributor.advisorYu, Hongtaoen
dc.contributor.committeeMemberNijhawan, Deepaken
dc.contributor.committeeMemberBrown, Michael S.en
dc.contributor.committeeMemberReady, Joseph M.en
dc.contributor.committeeMemberChen, Zhijian J.en
dc.creatorTheodoropoulos, Panayotis Christosen
dc.creator.orcid0000-0001-7393-2560
dc.date.accessioned2019-06-03T20:35:32Z
dc.date.available2019-06-03T20:35:32Z
dc.date.created2019-05
dc.date.issued2019-01-31
dc.date.submittedMay 2019
dc.date.updated2019-06-03T20:35:33Z
dc.description.abstractA hallmark of targeted cancer therapies is selective toxicity among cancer cell lines. We evaluated results from a viability screen of over 200,000 small molecules to identify two chemical series, oxalamides and benzothiazoles, that were selectively toxic to the same four of 12 lung cancer cell lines at low nanomolar concentrations. Sensitive cell lines expressed cytochrome P450 (CYP) 4F11, which metabolized the compounds into irreversible stearoyl CoA desaturase (SCD) inhibitors. SCD has been recognized as a promising biological target in cancer and metabolic disease. However, SCD is essential to sebocytes, and accordingly SCD inhibitors cause skin toxicity. Mouse sebocytes were unable to activate the benzothiazoles or oxalamides into SCD inhibitors, providing a therapeutic window for inhibiting SCD in vivo. We thus offer a strategy to target SCD in cancer by taking advantage of high CYP expression in a subset of tumors.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1103324615
dc.identifier.urihttps://hdl.handle.net/2152.5/6623
dc.language.isoenen
dc.subjectAntineoplastic Agentsen
dc.subjectBenzothiazolesen
dc.subjectDrug Discoveryen
dc.subjectLung Neoplasmsen
dc.subjectOxamic Aciden
dc.subjectStearoyl-CoA Desaturaseen
dc.titleElucidation of the Mechanism of Action of a Cell Line Selective Toxinen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineBiological Chemistryen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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