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Title Targeted histone deacetylase inhibition
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Publication Date
Date Accessioned
Degree PhD
Discipline/Department Chemistry and Biochemistry
Degree Level doctoral
University/Publisher Georgia Tech
Abstract Histone 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.
Subjects/Keywords HDAC inhibitors; Drug design; Targeted drug delivery; HDAC; Histone deacetylase; Bifunctional inhibitors; Cancer therapy; Drug delivery systems; Cancer Treatment; Enzymes
Contributors Yomi Oyelere (Committee Chair); Donald Doyle (Committee Member); James Powers (Committee Member); Loren Williams (Committee Member); Yuhong Fan (Committee Member)
Country of Publication us
Record ID handle:1853/44907
Repository gatech
Date Indexed 2020-05-13
Issued Date 2012-07-03 00:00:00
Note [degree] PhD; [advisor] Committee Chair: Yomi Oyelere; Committee Member: Donald Doyle; Committee Member: James Powers; Committee Member: Loren Williams; Committee Member: Yuhong Fan;

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