Small molecule inhibitors of triple negative breast cancer




McCowen, Shelby

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Among 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.


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EYA2, eyes absent phosphatase, Texas Torchwood, triple negative breast cancer