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dc.contributor.authorGuerrant, Williamen_US
dc.date.accessioned2012-09-20T18:24:11Z
dc.date.available2012-09-20T18:24:11Z
dc.date.issued2012-07-03en_US
dc.identifier.urihttp://hdl.handle.net/1853/44907
dc.description.abstractHistone deacetylase (HDAC) inhibitors (HDACi) have demonstrated a wealth of biological effects, including anti-proliferative, anti-inflammatory, anti-parasitic, and cognition-enhancing activities. The recent FDA approvals of the inhibitors SAHA and FK-228 have validated HDACi clinical use in cutaneous T cell lymphoma, while numerous clinical trials are currently ongoing using HDACi against a variety of disease states. While the future of the HDAC field looks increasingly promising, there are lingering issues hindering broader use. Recent data point to dysregulation of specific HDAC isoforms in many disease states. However, most current HDACi are pan-inhibitors, lacking the specificity to target individual isoforms. Adding to this, there are currently 18 identified HDAC isoforms, and most lack a defined crystal structure, further complicating the task of designing isoform-specific inhibitors. Most importantly, HDACi have demonstrated a lack of efficacy against solid tumors in the clinic, a major obstacle to broader use in cancer therapy. Several of these issues could more fully be addressed through specific targeting of HDACi, and could bring HDACi into wider and more efficacious pharmaceutical use. Targeting the specific tissue or organelle where HDAC dysregulation occurs could confer greater efficacy in vivo. To this end, we have created four classes of compounds: (1) aryltriazolyl HDACi that potently inhibit HDAC activity and prostate cancer cell growth, (2) dual-targeted inhibitors of Topoisomerase II and HDAC and (3) dual-targeted inhibitors of Topoisomerase I and HDAC, both of which have potent inhibition against both target enzymes as well as cancer cell lines, and finally (4) macrocyclic HDACi that potently inhibit the growth of lung cancer cell lines and preferentially target lung tissue in vivo.en_US
dc.publisherGeorgia Institute of Technologyen_US
dc.subjectHDAC inhibitorsen_US
dc.subjectDrug designen_US
dc.subjectTargeted drug deliveryen_US
dc.subjectHDACen_US
dc.subjectHistone deacetylaseen_US
dc.subjectBifunctional inhibitorsen_US
dc.subjectCancer therapyen_US
dc.subject.lcshDrug delivery systems
dc.subject.lcshCancer Treatment
dc.subject.lcshEnzymes
dc.titleTargeted histone deacetylase inhibitionen_US
dc.typeDissertationen_US
dc.description.degreePhDen_US
dc.contributor.departmentChemistry and Biochemistryen_US
dc.description.advisorCommittee Chair: Yomi Oyelere; Committee Member: Donald Doyle; Committee Member: James Powers; Committee Member: Loren Williams; Committee Member: Yuhong Fanen_US


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