A new class of small molecule estrogen receptor-alpha antagonists that overcome anti-estrogen resistance.

ABSTRACT: Previous studies indicate that BRCA1 protein binds to estrogen receptor-alpha (ER) and inhibits its activity. Here, we found that BRCA1 over-expression not only inhibits ER activity in anti-estrogen-resistant LCC9 cells but also partially restores their sensitivity to Tamoxifen. To simulate the mechanism of BRCA1 inhibition of ER in the setting of Tamoxifen resistance, we created a three-dimensional model of a BRCA1-binding cavity within the ER/Tamoxifen complex; and we screened a pharmacophore database to identify small molecules that could fit into this cavity. Among the top 40 "hits", six exhibited potent ER inhibitory activity in anti-estrogen-sensitive MCF-7 cells and four of the six exhibited similar activity (IC50 ≤ 1.0 μM) in LCC9 cells. We validated the model by mutation analysis.

SUBMITTER: Ma Y 

PROVIDER: S-EPMC4747340 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature