jm7b01228_si_002.csv (1.62 kB)
Structure–Activity Relationships of New Natural Product-Based Diaryloxazoles with Selective Activity against Androgen Receptor-Positive Breast Cancer Cells
datasetposted on 2017-10-20, 00:00 authored by Andrew J. Robles, Shelby McCowen, Shengxin Cai, Michaels Glassman, Francisco Ruiz, Robert H. Cichewicz, Stanton F. McHardy, Susan L. Mooberry
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.
HER 2. Gene expressionAndrogen Receptor-Positive Breast Cancer Cells Targeted therapieslack expressiontherapymTORC 1 pathwayplant Amyris texanaaction studies showanalog synthesiscell linepatient survivalrepresentative cell linesantiproliferative activitiesSelective ActivityHER 2-amplified breast cancersluminal androgen receptorcompound 30TNBCLAR subtype cell line modelsbreast cancersprogesterone receptorsNew Natural Product-Based DiaryloxazolesCIDDMDA-MB -453 cellsBioassay-guided fractionation