Probing androgen receptor co-factor selectivity profiles: a chemical tool to determine cross-talk between androgen receptor and β-catenin in vivo

MedChemComm Pub Date: 2013-01-14 DOI: 10.1039/C3MD20341G

Abstract

Previous reports on Selective Androgen Receptor Modulators (SARMs) have described their activity primarily by their tissue selectivity in animal models. A few SARMs have been described with tissue selectivity ascribed to their diminished activity in promoting the intramolecular interaction between the androgen receptor (AR) carboxyl and amino termini. In the current study we characterized an AR ligand PF-05314882 that has an unusual in vitro selectivity profile in AR cell based assays. This SARM was previously reported to have tissue selective AR activity in rats. In the current study PF-05314882 bound to the AR ligand binding domain with good affinity and activated AR-mediated transcription in vitro. However, unlike naturally occurring androgens and other SARMs, PF-05314882 does not stimulate interaction between AR and β-catenin. Consistent with this observation, PF-05314882 had only weak activity on androgen-AR dependent inhibition of Wnt reporter activity. In castrated rats, the daily administration of PF-05314882 had anabolic activity on increasing levator ani muscle weight and elevating RNA expression of androgen regulated metabolic genes in the liver. Similar to previously described tissue selective SARMs, PF-05314882 has very little activity in the prostate, seminal vesicles and in repressing circulating luteinizing hormone (LH) levels. More importantly, since AR and β-catenin have been shown to play important roles in overlapping tissues including adipose, bone, hair and in diseases such as prostate cancer, PF-05314882 may be an important pharmacologic tool to elucidate the role and extent of cross-talk between AR and β-catenin.

Graphical abstract: Probing androgen receptor co-factor selectivity profiles: a chemical tool to determine cross-talk between androgen receptor and β-catenin in vivo
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