Molecular Determinants of Androgen Receptor Pharmacology

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DESCRIPTION (provided by applicant): Until recently the molecular pharmacology of the human androgen receptor (hAR) was considered to be relatively simple. Compounds like dihydrotestosterone (DHT) functioned as agonists by binding to and inducing a change in receptor structure. This activating conformational change initiated a series of events that led to the interaction of the receptor with specific DNA sequences within target genes. In the DNA bound state the receptor was able to couple with the proteins and processes required for its transcriptional regulatory activities. In these established models of AR action, antagonists were believed to function solely by competitively inhibiting the interaction of agonists with the receptor. However, as with other receptors, notably the estrogen, progesterone and glucocorticoid receptors, the pharmacology of AR is now believed to be more complex and in general appears to be a function of (a) the expression level of the receptor, (b) the effect of the bound ligand on receptor structure, (c) the ability of differently conformed ligand-receptor pairs to engage coactivators and corepressors and (d) the relative expression level of coactivators and corepressors in different cells. In this grant we propose a series of studies with the objective of defining how information flows from an AR ligand to its receptor and subsequently to target genes. This will be accomplished in a study with three specific aims; (1) Identification of surfaces exposed on AR in the presence of different ligands (2) Definition of the functional significance of the surfaces on AR implicated by the peptide binding studies and (3) Identification of the proteins that interact with functionally important surfaces on AR. It is anticipated that at the conclusion of these studies we will have a better understanding of the molecular mechanism of action of the currently available AR agonists and antagonists. In addition these studies may suggest ways to exploit the complexity of the AR signaling pathways for the development of Selective Androgen Receptor Modulators (SARMs) for use in the treatment of a variety of androgenopathies.