Skip to main content
Home Whitman College Penrose Library | Arminda Collections

Main menu

  • Home
  • Browse Collections
  • About
  • Login
  1. Home
  2. Honors Theses
  3. Synthesis and evaluation of peptidic epoxyketone inhibitors targeting the human 20S proteasome
Title

Synthesis and evaluation of peptidic epoxyketone inhibitors targeting the human 20S proteasome

    Item Description
    Limited Access
    The author(s) chose to restrict access to this thesis to current Whitman students, faculty, and staff. Please log in to view it.
    Linked Agent
    Creator (cre): Price, Rachel Marie
    Advisor (adv): Götz, Marion
    Department (dpt): Whitman College. Biochemistry, Biophysics and Molecular Biology
    Date
    May 7, 2019
    Graduation Year
    2019
    Abstract

    A multicatalytic proteolytic complex, the proteasome is responsible for hydrolyzing intracellular proteins and is a common chemotherapeutic target in the treatment of multiple myeloma due to its role in degrading vital cell cycle proteins. Cyclins and tumor suppressors such as p53 accumulate as a result of proteasome inhibition, inducing cell cycle arrest or apoptosis. Multiple myeloma is clinically treated with proteasome inhibitors like carfilzomib, which causes an array of severe side-effects due to lack of proteasomal specificity. The inhibitor proposed in this research combines the potent epoxyketone electrophilic trap from carfilzomib with a rigid macrocyclic moiety derived from the fungal metabolite TMC-95A; the macrocycle contributes to both the potency and selectivity of the inhibitor. The proposed peptidic inhibitor aims to optimize the efficacy of inhibition while increasing selectivity. This study confirmed that the epoxyketone electrophilic trap increases inhibitory potency when compared to amide inhibitors previously synthesized by this research group. Additionally, the formation of essential hydrogen bonds between the oxindole incorporated from TMC-95A and the active site were confirmed by X-ray crystallography. Along with epoxyketone inhibitors, this research introduces the aldoxime electrophilic trap as a potential candidate for proteasomal inhibition.

    Subject
    Proteasome Endopeptidase Complex
    Proteasome Inhibitors
    Multiple myeloma
    Carfilzomib
    Epoxy compounds
    Electrophiles
    Macrocyclic compounds
    Metabolites -- TMC-95A
    Moieties
    Science
    Academic theses
    Whitman College 2019 -- Dissertation collection -- Biochemistry, Biophysics, and Molecular Biology
    Genre
    Theses
    Extent
    55 pages
    Permanent URL
    http://works.whitman.edu/2019025
    Rights
    http://rightsstatements.org/vocab/InC/1.0/
    Contact Us

    If you have questions about permitted uses of this content, please contact the Arminda administrator: http://works.whitman.edu/contact-arminda

    THESIS_2019_1102362993_001
    Home Whitman College Penrose Library | Arminda Collections

    Footer menu

    • About
    • Author FAQ
    • Contact Us
    • List of Collections
    • Policies
    • Terms of Use