Structure–Activity Relationships of New Natural Product-Based Diaryloxazoles with Selective Activity against Androgen Receptor-Positive Breast Cancer Cells

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.