Molecular mechanism of novel androgen receptor agonists

Duke University, Durham NC

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Abstract

DESCRIPTION (provided by applicant): In this proposal I will study the molecular mechanism of action of the prototype selective androgen receptor modulators (SARMs) we have identified. These androgen receptor ligands are unique because they appear to induce conformational changes in androgen receptor which are different from those induced by full agonists. My preliminary data indicates that these compounds show promoter specificities different from that of full agonists, which allows looking at them as candidate selective androgen receptor modulators - SARMs. To characterize the mechanism of action of these compounds, will first establish the gene expression patterns attributable to each compound, focusing on the two relatively well established arenas of androgen action: prostate epithelium proliferation and regulation of fat and cholesterol metabolism. I will then move to identify the protein-protein interaction surfaces exposed on AR when liganded with each of these compounds. Finally, I will establish the link between exposed surfaces on AR and ligand-specific transcriptional regulation.