Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.630242
Title: Chemical genetic screen for inhibitors of human telomerase
Author: Wong, Lai Hong
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2013
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Abstract:
There 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.
Supervisor: Harrington, Lea; Interthal, Heidrun Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.630242  DOI: Not available
Keywords: telomerase disruption ; S. cerevisiae ; telomerase inhibitors
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