The Design, Synthesis, and Optimization of Di-Aryloxazole Inhibitors for the Treatment of Triple-Negative Breast Cancer




Glassman, Michaels Garnett

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Triple-negative breast cancer (TNBC) accounts for 10-15% of all total breast cancer cases, but has a much lower survival rate than its hormone-receptor counterparts. Currently, TNBC is treated with surgery, radiation, or chemotherapies – however no targeted therapies have been developed which present an unmet medical need. Based on two natural products isolated from the Mooberry lab which demonstrate inhibition in luminal androgen receptor (LAR) TNBC lines, and guided by a robust structure-activity relationship (SAR) program, we have identified two lead compounds after four generations of molecular tuning. These two lead compounds, 63c and 72c, exhibit an increase of >150-fold potency and >200-fold selectivity towards LAR TNBC lines compared to the isolated natural products. SAR studies have been conducted around a majority of the chemical space of our lead compounds, however there is still room for further optimization. Based on this work, this thesis is organized into four chapters; 1) SAR studies on the 4-alkoxy aryl ring and phenol, tertiary amine salt handles, and synthesis of regiochemical controls, 2) SAR studies of the prolinamide series and oxazole regiochemical outcomes, 3) SAR studies of the heterocyclic core, and 4) Synthesis of small-molecule probes for target elucidation.


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Triple-negative breast cancer, Luminal androgen receptor, Regiochemical controls, Small-molecule probes