Small molecule inhibitors of triple negative breast cancer

dc.contributor.advisorMcHardy, Stanton
dc.contributor.authorMcCowen, Shelby
dc.contributor.committeeMemberFrantz, Douglas
dc.contributor.committeeMemberDoyle, Michael
dc.date.accessioned2024-02-12T15:40:16Z
dc.date.available2024-02-12T15:40:16Z
dc.date.issued2016
dc.descriptionThis item is available only to currently enrolled UTSA students, faculty or staff. To download, navigate to Log In in the top right-hand corner of this screen, then select Log in with my UTSA ID.
dc.description.abstractAmong women who are afflicted with breast cancer, 15-20% have the triple negative subtype which lacks estrogen, progesterone and human epidermal growth factor 2 receptors. Treating triple negative breast cancer still remains a large issue due to the lack of potent and selective chemotherapies. Recent studies have demonstrated that EYA2 inhibits ERβ through its actions as a tyrosine phosphatase, providing a new therapeutic target. Herein described are two series of small molecules that inhibit the EYA2 phosphatase function. The first series is based off a thiazolone core and is thought to bind to the active site of EYA2; the lead compound, CIDD-0066849, displays IC50 values of 10.5 and 0.33 µM for EYA2 and cell proliferation inhibition, respectively. A second series of allosteric acyl hydrazone inhibitors of the EYA2 phosphatase, which also display growth inhibition of the EYA2 over-expressing triple negative cancer cell line MDA-MB-468, has also been explored. The most potent lead, CIDD-0067079, displayed an IC50 of 7.0 and 4.8 µM for inhibition of EYA2 phosphatase and cell proliferation, respectively. A second small molecule series was developed based off of two natural products isolated from Texas Torchwood that selectively inhibits the growth of the triple negative breast cancer cell line MDA-MB-453. Three generations of SAR analysis have resulted in the lead compound CIDD-0067107 with a less than 100 nM inhibition of cell growth while maintaining selectivity for MDA-MB-453. All together, these small molecules could provide new, targeted therapies for triple negative breast cancer. While they would not be able to treat all cases, in those patients who would be susceptible, they may provide treatment with fewer side effects.
dc.description.departmentChemistry
dc.format.extent82 pages
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/20.500.12588/4633
dc.languageen
dc.subjectEYA2
dc.subjecteyes absent phosphatase
dc.subjectTexas Torchwood
dc.subjecttriple negative breast cancer
dc.subject.classificationOrganic chemistry
dc.subject.classificationChemistry
dc.titleSmall molecule inhibitors of triple negative breast cancer
dc.typeThesis
dc.type.dcmiText
dcterms.accessRightspq_closed
thesis.degree.departmentChemistry
thesis.degree.grantorUniversity of Texas at San Antonio
thesis.degree.levelMasters
thesis.degree.nameMaster of Science

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