Chemically Based Interrogation of Smoothened, a Proto-Oncogenic Component of the Hedgehog Signal Transduction Pathway

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dc.contributor.advisorRoth, Michael G.en
dc.contributor.committeeMemberLum, Lawrenceen
dc.contributor.committeeMemberParada, Luis F.en
dc.contributor.committeeMemberMacMillan, Johnen
dc.creatorFan, Chih-Wei 1982-en
dc.date.accessioned2015-01-13T23:31:52Z
dc.date.available2015-01-13T23:31:52Z
dc.date.created2012-12
dc.date.issued2012-11-28
dc.date.submittedDecember 2012
dc.date.updated2015-01-13T23:31:18Z
dc.description.abstractAberrant activation of the Hedgehog (Hh) signal transduction pathway is crucial for the initiation and maintenance of many cancer types. Underlying this deviant signaling process in most cases of cancer is genetic mutations that give rise to misactivation of the seven transmembrane oncoprotein, Smoothened (Smo). Thus, Smo is a high priority therapeutic target in Hh-associated cancers including basal cell carcinoma (BCC) and medulloblastoma. While a Smo antagonist is now approved for the management of BCC, therapeutic strategies focused on Smo continue to encounter issues of intrinsic and acquired drug resistance. To overcome these challenges, I executed a small molecule screen in order to identify novel druggable components in the Hh pathway, and to elucidate new chemical scaffolds that exhibit unique activities against an oncogenic form of Smo, SmoM2. My in-depth interrogation of a novel Smo antagonist identified from this screen called Inhibitor of Hh response 1 (IHR1) revealed mechanisms that enable SmoM2 to bypass a signaling checkpoint imposed by the cellular antenna-like structure known as the primary cilium. Furthermore, this deviant form of signaling from an intracellular compartment shelters SmoM2 from chemical attack thus rendering it intrinsically resistant to certain Smo antagonists. Based on this new understanding of SmoM2 signaling, I was able to evolve second-generation IHR1 compounds with improved anti-Hh pathway activity thus revealing a general chemical strategy for improving Smo antagonist-based therapy. From this study, I also gained new insights into the role of the primary cilium in supporting homeostatic cellular signal transduction processes.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc900282180
dc.identifier.urihttps://hdl.handle.net/2152.5/ETD-UTSWMED-2012-12-58
dc.identifier.urihttps://hdl.handle.net/2152.5/1471
dc.language.isoenen
dc.subjectHedgehog Proteinsen
dc.subjectReceptors, G-Protein-Coupleden
dc.subjectSignal Transductionen
dc.titleChemically Based Interrogation of Smoothened, a Proto-Oncogenic Component of the Hedgehog Signal Transduction Pathwayen
dc.typeThesisen
dc.type.materialTexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineCancer Biologyen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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