@article{d3dce3fa7d1940a49b3971d790f9128c,
title = "Structure-Activity Relationships of New Natural Product-Based Diaryloxazoles with Selective Activity against Androgen Receptor-Positive Breast Cancer Cells",
abstract = "Targeted therapies for ER+/PR+ and HER2-amplified breast cancers have improved patient survival, but there are no therapies for triple negative breast cancers (TNBC) that lack expression of estrogen and progesterone receptors (ER/PR), or amplification or overexpression of HER2. Gene expression profiling of TNBC has identified molecular subtypes and representative cell lines. An extract of the Texas native plant Amyris texana was found to have selective activity against MDA-MB-453 cells, a model of the luminal androgen receptor (LAR) subtype of TNBC. Bioassay-guided fractionation identified two oxazole natural products with selective activity against this cell line. Conducted analog synthesis and structure-activity relationship studies provided analogs with more potent and selective activity against two LAR subtype cell line models, culminating in the discovery of compound 30 (CIDD-0067106). Lead compounds discovered have potent and selective antiproliferative activities, and mechanisms of action studies show they inhibit the activity of the mTORC1 pathway.",
author = "Robles, {Andrew J.} and Shelby McCowen and Shengxin Cai and Michaels Glassman and Francisco Ruiz and Cichewicz, {Robert H.} and McHardy, {Stanton F.} and Mooberry, {Susan L.}",
note = "Funding Information: ∇Harris County Institute of Forensic Sciences, Houston, Texas 77054, United States. Author Contributions A.J.R. and S.L.M. designed the biological experiments, and A.J.R. conducted them. S.F.M. and S.M. designed all analogs and planned all chemistry experiments and compound synthesis. S.M. synthesized and characterized all compounds and analogs. M.G. developed alternative synthesis routes. S.C. and R.H.C. planned the isolation of the natural products. S.C. isolated the natural products and determined their structures. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding This study was funded by grants to S.L.M. and R.H.C. from the National Cancer Institute (UO1CA182740), the UTHSCSA President{\textquoteright}s Council Excellence Award (to S.L.M), and the Greehey Distinguished Chair in Targeted Molecular Therapeutics endowment (to S.L.M.). Support of the Flow Cytometry, Macromolecular Structure, and Mass Spectrometry Shared Resources of the CTRC Cancer Center Support Grant (P30 CA054174) are gratefully acknowledged. A.J.R was partially supported by the IMSD program of the NIGMS (1R25GM095480-01). Medicinal chemistry support from the Cancer Prevention Research Institute of Texas (CPRIT) grant RP160844 (to S.F.M) is gratefully acknowledged. Notes The authors declare no competing financial interest.",
year = "2017",
month = nov,
day = "22",
doi = "10.1021/acs.jmedchem.7b01228",
language = "English (US)",
volume = "60",
pages = "9275--9289",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "22",
}