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    The Development of Small Molecules that Modulate Molecular Chaperones Hsp90 and Hsp70

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    Forsberg_ku_0099D_15671_DATA_1.pdf (22.96Mb)
    Issue Date
    2017-12-31
    Author
    Forsberg, Leah Kathleen
    Publisher
    University of Kansas
    Format
    390 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Medicinal Chemistry
    Rights
    Copyright held by the author.
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    Abstract
    The heat shock proteins are a highly conserved protein family that are constitutively expressed and function as molecular chaperones. Molecular chaperones 90kDa Heat Shock Protein (Hsp90) and 70kDa Heat Shock Protein (Hsp70) have emerged as promising therapeutic targets for both cancer and neurodegenerative diseases. Hsp90 is responsible for the maturation of more than 300 nascent polypeptides, “clients”. These client proteins are involved in the oncogenic process, as many are associated with all 10 hallmarks of cancer. Hsp70 is involved in protein folding and maintenance of protein homeostasis. Targeting molecular chaperones, Hsp70 and Hsp90, is a viable therapeutic strategy for various neurodegenerative diseases as they prevent protein aggregation via refolding denatured proteins and solubilizing protein aggregates. Therefore, small molecules that interact with Hsp90 are sought, as modulation of Hsp90 can impact the cellular function of Hsp70. Hsp90 contains a traditional N-terminal ATP-binding site and a C-terminal dimerization domain, which contains an additional binding site. Targeting the Hsp90 C-terminus with inhibitors derived from novobiocin is one approach to modulating molecular chaperones. Structure activity relationship studies on novobiocin have led to the development of either neuroprotective or cytotoxic compounds. Segregation of the pro-survival heat shock response from a cytotoxic response due to client protein degradation is unique to C-terminal inhibitors. Described herein is the design, synthesis and biological evaluation of small molecules that target the C-terminus of Hsp90, for the continued development of potential therapeutics for the treatment of cancer or neurodegenerative diseases.
    URI
    http://hdl.handle.net/1808/26159
    Collections
    • Dissertations [4475]
    • Medicinal Chemistry Dissertations and Theses [80]

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    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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