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    Interrogation of Small Molecule Therapeutics for BRCA Deficient Cancers

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    Genre
    Thesis/Dissertation
    Date
    2020
    Author
    Hewlett, Elizabeth D.
    Advisor
    Childers, Wayne E.
    Committee member
    Abou-Gharbia, Magid
    Canney, Daniel J.
    Blass, Benjamin E.
    Ott, Gregory R.
    Department
    Pharmaceutical Sciences
    Subject
    Pharmaceutical Sciences
    5f02
    Brca Deficient Cancers
    Cis-decalin
    Hrr
    Parp1
    Rad52
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/3005
    
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    DOI
    http://dx.doi.org/10.34944/dspace/2987
    Abstract
    This thesis focuses on the development of molecules that target proteins in a previously undescribed manner for the treatment of BRCA deficient cancers. ZINC 13403027, a clerodan-based natural product, was shown to target a protein called Rad52. Cancers possessing loss of function mutations in BRCA1 and BRCA2 are dependent on Rad52 for DNA repair and replication while normal, healthy cells possess multiple DNA repair/replication pathways. Thus, inhibitors of Rad52 may serve as selective anti-cancer drugs for BRCA deficient tumors. ZNIC 13403027 was selected for its high activity in disrupting the ssDNA-Rad52 interaction in a gel-shift assay as well as exhibiting the required inactivity at disrupting the ssDNA-Rad51 interaction. Due to its lack of permeability, a synthetic route amenable to modification has been partially developed. It is thought that a prodrug or bioisostere of ZINC 13403027 could cross the membrane so that the cellular activity of this novel tool molecule may be established. Additionally, an allosteric PARP1 inhibitor, 5F02, was explored. Discussed here is the synthetic route to 5F02 and its analogs. Structure activity relationships were develop in an attempt to increase inhibitory activity and drug-like properties. This thesis reports the success to date on these two projects.
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