Georgetown University LogoGeorgetown University Library LogoDigitalGeorgetown Home
    • Login
    View Item 
    •   DigitalGeorgetown Home
    • Georgetown University Institutional Repository
    • Georgetown University Medical Center
    • Lombardi Comprehensive Cancer Center
    • Program of Tumor Biology
    • Graduate Theses and Dissertations - Tumor Biology
    • View Item
    •   DigitalGeorgetown Home
    • Georgetown University Institutional Repository
    • Georgetown University Medical Center
    • Lombardi Comprehensive Cancer Center
    • Program of Tumor Biology
    • Graduate Theses and Dissertations - Tumor Biology
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    EWS-­FLI1 as a molecular target: Small molecule inhibitors for a disordered protein

    Cover for EWS-­FLI1 as a molecular target: Small molecule inhibitors for a disordered protein
    View/Open
    View/Open: BarberRotenberg_georgetown_0076D_11779.pdf (14.MB) Bookview

    Creator
    Barber-Rotenberg, Julie
    Advisor
    Toretsky, Jeffrey A
    Abstract
    Ewing sarcoma family of tumors (ESFT) consists of highly malignant tumors of the bone and soft tissue. Ninety-five percent of cases contain a balanced t(11;22) or t(21;22) rearrangement, combining the amino-terminus of EWS to the carboxy-terminus of FLI1 or ERG, which contain the highly conserved ets DNA binding domain. As the EWS-FLI1 protein is found only in ESFT cells and its expression is required for the oncogenic phenotype, it presents a promising molecular target for anti-cancer therapies. EWS-FLI1 is a hydrophobic disordered protein with unknown three-dimensional structure, precluding standard structure-based drug design. RNA Helicase A (RHA) enhances EWS-FLI1 driven oncogenesis and interruption of this protein-protein complex validates this interaction as a unique therapeutic target. Surface plasmon resonance screening identified compounds that bind to EWS-FLI1, including a lead compound that induces apoptosis in ESFT cells and reduces the growth of xenografts. Our compound, YK-4-279, has a chiral center and can be separated into enantiomers, only one of which is able to specifically target the protein-protein interaction. This work is significant for its identification of a single enantiomer effect upon a protein-protein interaction suggesting that small molecule targeting of intrinsically disordered proteins can be highly specific. Given the challenges of drug design targeted to EWS-FLI1, we proposed that characterization of the physical interaction points between EWS-FLI1 and RHA would allow us to better alter the lead compound to block this protein-protein interaction. While full length EWS-FLI1 is able to pull down RHA, fragments of the protein are not. Although we can successfully crosslink EWS-FLI1 and RHA, we have yet to identify what region of EWS-FLI1 is involved. We are able to show specific regions of order and disorder of EWS-FLI1, which may lead to the identification of the binding site for YK-4-279. The development of higher-throughput methods for testing small molecules that bind to or inhibit EWS-FLI1 function will allow us to further investigate protein structure and function. These data are a contribution to the future development of small molecules in an era where novel approaches to cancer therapy are critical for improving patient care.
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/557903
    Date Published
    2012
    Subject
    disordered protein; EWS-FLI1; small molecule; Oncology; Biochemistry; Oncology; Biochemistry;
    Type
    thesis
    Publisher
    Georgetown University
    Extent
    136 leaves
    Collections
    • Graduate Theses and Dissertations - Tumor Biology
    Metadata
    Show full item record

    Related items

    Showing items related by title, author, creator and subject.

    • Cover for Amino-acid derived 1,2 benzisothiazolinone derivatives as novel small molecule antifungal inhibitors: Characterization and identification of potential genetic targets

      Amino-acid derived 1,2 benzisothiazolinone derivatives as novel small molecule antifungal inhibitors: Characterization and identification of potential genetic targets 

      Alex, Deepu (Georgetown University, 2011)
      A steady increase in the incidence of fungal infections has been observed over the past few decades, and treatment remains challenging especially for immuno-compromised populations. Identification of the ideal therapeutic ...
    Related Items in Google Scholar

    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility
     

     

    Browse

    All of DigitalGeorgetownCommunities & CollectionsCreatorsTitlesBy Creation DateThis CollectionCreatorsTitlesBy Creation Date

    My Account

    Login

    Statistics

    View Usage Statistics

    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility