Investigation of the Hsp90 C-terminal Binding Site, Novel Inhibitors and Isoform-Dependent Client Proteins
Issue Date
2012-08-31Author
Peterson, Laura B.
Publisher
University of Kansas
Format
204 pages
Type
Dissertation
Degree Level
Ph.D.
Discipline
Medicinal Chemistry
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This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
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Show full item recordAbstract
The heat shock proteins represent an important class of pro-survival proteins that are intimately involved in cell survival, adaptation to cellular stress, and protein management. Heat shock protein 90 kDa (Hsp90) is a molecular chaperone responsible for the post-translational maturation of nascent polypeptides. Many of the Hsp90-dependent client proteins are involved in oncogenic processes, and accordingly, Hsp90 has emerged as a promising target for anti-cancer therapies. Unfortunately, the clinical evaluation of Hsp90 inhibitors has been met with dosing, scheduling, and toxicity issues. The Hsp90 inhibitors that have reached clinical trials bind to the Hsp90 N-terminal ATP-binding site and demonstrate pan-Hsp90 inhibition, as they bind to and inhibit all four human Hsp90 isoforms. This characteristic may rationalize the undesired toxicities related to Hsp90 inhibition. Interestingly, the identification and characterization of isoform specific client proteins has not been extensively explored. In addition, N-terminal Hsp90 inhibition results in the induction of the heat shock response, whereby the expression of Hsp90 and other heat shock proteins is induced. This attribute of N-terminal inhibitors results in the clinically observed dosing and scheduling detriments as levels of Hsp90 increase with administration of the drug. Described herein is the design, synthesis and biological evaluation of novel Hsp90 inhibitors that avoid the above mentioned therapeutic liabilities of currently known Hsp90 inhibitors. The identification and characterization of an Hsp90-isoform dependent client protein and an Hsp90-isoform selective inhibitor is also presented.
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