Design, Synthesis and Biological Evaluation of Ring-constrained and Biphenyl Derivatives as Hsp90 C-terminal Inhibitors

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Issue Date
2014-05-31Author
Garg, Gaurav
Publisher
University of Kansas
Format
165 pages
Type
Thesis
Degree Level
M.S.
Discipline
Medicinal Chemistry
Rights
Copyright held by the author.
Metadata
Show full item recordAbstract
Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone that plays a pivotal role in protein homeostasis in responses to cellular stress. Hsp90 regulates the conformational maturation, activation, and integrity of a wide array of client proteins, including oncogenic proteins (Her2, Raf1, Akt, CDK4 etc.) associated with all six hallmarks of cancer. Consequently, Hsp90 inhibition offers a unique opportunity for the simultaneous degradation of multiple anti-cancer targets and hence, for the development of cancer chemotherapeutics. Hsp90 exists as a homodimer with each monomer consisting of a druggable domain; the N-terminal domain, the middle domain, and the C-terminus. The majority of research has focused on development of Hsp90 N-terminal inhibitors. In fact, all Hsp90 inhibitors in clinical trials belong to this class. One of the major drawbacks associated with N-terminal inhibitors is the concomitant induction of the pro-survival response, which results in an upregulation of Hsp's and affects the dosing schedule. As a result, alternative strategies are sought for the development of future Hsp90 inhibitors. Over the last decade, Hsp90 C-terminal inhibitors have emerged an attractive alternative for Hsp90 modulation. These inhibitors exhibit similar inhibitory activity to N-terminal inhibitors, but do not induce the pro-survival response and could potentially circumvent the clinical limitations imposed on N-terminal Inhibitors. Presented herein are the design, synthesis and biological evaluation of ring-constrained novobiocin analogues that provide new insights into the Hsp90 C-terminal binding pocket and SAR's that can be used for future analog development. In addition, identification of a novel class of Hsp90 inhibitors is discussed. These new agents provide a platform upon which future Hsp90 inhibitors can be built upon.
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- Medicinal Chemistry Dissertations and Theses [80]
- Theses [3906]
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