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dc.contributor.advisorHarrington, Lea
dc.contributor.advisorInterthal, Heidrun
dc.contributor.authorWong, Lai Hong
dc.date.accessioned2014-10-13T15:25:03Z
dc.date.available2014-10-13T15:25:03Z
dc.date.issued2013-06-29
dc.identifier.urihttp://hdl.handle.net/1842/9524
dc.description.abstractThere remains a pressing need for the development of effective drugs that meet the clinical needs for cancer treatment, and inhibition of telomere length maintenance by disrupting human telomerase is a proven and tractable target for suppression of cancer cell growth. In response to the lack of currently available small molecules with efficacy against human telomerase, we developed a genetically and chemically tractable cell-based system in which S. cerevisiae is used to streamline the search for novel human telomerase inhibitors. Our results confirmed that yeast cell growth was rapidly inhibited upon induction of functional human telomerase at the telomere. This inducible growth arrest was used as a read-out for a high-throughput chemical screen for human telomerase inhibitors based on their ability to restore growth in the yeast system. From a library consisting of small, bioactive and cell-permeable compounds of diverse structure, we identified three novel “drug-like” compounds that inhibited the activity of native and recombinant telomerase complexes in vitro. “Validation assays” also confirmed the novel inhibitors were free of uncharacterized adverse effects against yeast and human cell models, thus confirming the specificity of these novel inhibitors against human telomerase target. This surrogate yeast model has therefore proven to be a cost-effective alternative to accelerate the search for human telomerase inhibitors, which we hope will serve to streamline the identification of further lead compounds effective against human cancer.en_US
dc.language.isoenen_US
dc.publisherThe University of Edinburghen_US
dc.relation.hasversionChemistry & Biology: Lai H. Wong, Asier Unciti-Broceta, Michaela Spitzer, Rachel White, Mike Tyers, Lea Harrington. ‘A yeast chemical genetic screen identifies new inhibitors of human telomerase’.en_US
dc.subjecttelomerase disruptionen_US
dc.subjectS. cerevisiaeen_US
dc.subjecttelomerase inhibitorsen_US
dc.titleChemical genetic screen for inhibitors of human telomeraseen_US
dc.typeThesis or Dissertationen_US
dc.type.qualificationlevelDoctoralen_US
dc.type.qualificationnamePhD Doctor of Philosophyen_US


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