Development of chemical inducers of dimerization for screening competitive histone deactelyase inhibitors

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Aubie, Emily Lynn
ELISA; HDACi; Histone Deacetylase; yeast three hybrid; Biochemistry; Chemistry; Organic Chemistry
thesis / dissertation description
Histone Deacetylase (HDAC) proteins are transcriptional regulators that affect histone proteins, which are involved in packaging of DNA into chromosomes. HDACs have been linked to the proliferation of cancer through their role in transcriptional regulation. Due to these findings, HDAC inhibitors have been explored as anti-cancer agents. Several HDAC inhibitors are currently in various stages of clinical trials, and the inhibitor suberoyl anilide hydroxamic acid (SAHA) has been FDA approved for treatment of cutaneous T-Cell lymphoma. Currently, most of the known HDAC inhibitors are non-selective, which causes non-specific binding to the active sites of all HDAC isoforms, including those not involved in cancer. To date, screening for HDAC inhibitors has been done using an in vitro fluorescence-screening assay, which is unable to test for selectivity. Alternatively, HDAC inhibitors are screened against commercially produced proteins, which is very time consuming and can be prohibitively expensive. To improve the screening methods for HDAC inhibitors, we are developing an assay to screen HDAC inhibitors against individual isoforms in a high-throughput assay. The assay has been developed using a competitive bifunctional small molecule based on SAHA to test for inhibitor binding.