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dc.contributor.advisorChilders, Wayne E.
dc.creatorHewlett, Elizabeth D.
dc.date.accessioned2020-11-04T15:20:03Z
dc.date.available2020-11-04T15:20:03Z
dc.date.issued2020
dc.identifier.urihttp://hdl.handle.net/20.500.12613/3005
dc.description.abstractThis 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.
dc.format.extent257 pages
dc.language.isoeng
dc.publisherTemple University. Libraries
dc.relation.ispartofTheses and Dissertations
dc.rightsIN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available.
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectPharmaceutical Sciences
dc.subject5f02
dc.subjectBrca Deficient Cancers
dc.subjectCis-decalin
dc.subjectHrr
dc.subjectParp1
dc.subjectRad52
dc.titleInterrogation of Small Molecule Therapeutics for BRCA Deficient Cancers
dc.typeText
dc.type.genreThesis/Dissertation
dc.contributor.committeememberAbou-Gharbia, Magid
dc.contributor.committeememberCanney, Daniel J.
dc.contributor.committeememberBlass, Benjamin E.
dc.contributor.committeememberOtt, Gregory R.
dc.description.departmentPharmaceutical Sciences
dc.relation.doihttp://dx.doi.org/10.34944/dspace/2987
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.description.degreePh.D.
refterms.dateFOA2020-11-04T15:20:03Z


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