Earlier studies with SERMs identified

Earlier studies with SERMs identified that distinct chemical scaffolds have the ability to induce unique conformational changes in the ER, resulting in interaction with different cofactor subsets. The same has been demonstrated with SARMs, which induce distinct conformational changes compared to testosterone and DHT, resulting in complexes containing different coregulator complexes (Chang and McDonnell, 2002). Using combinatorial peptide-phage display, McDonnell and his colleagues elegantly showed that different ligands induce distinct AR and ER conformations leading to their association with varying coactivator peptides (Chang and McDonnell, 2002, Chang et al., 1999). The SARMs RTI-018 and RTI-001 possessed a spectrum of agonist activities and altered kinetics of response and these differences were attributed to SARM-mediated structural differences leading to the association of the AR with coactivator peptides distinct from DHT (Kazmin et al., 2006). In another study, the antagonist bicalutamide recruited corepressors SMRT and NCoR, but in the presence of IL-8 recruited coactivators thus adopting agonist features (Baek et al., 2006). This study confirms the findings that changes in conformation induced by an external stimulus can result in a shift in the transcriptional complex formed by the AR resulting in a change in activity. The role of coregulators in the tissue-selective action of synthetic rotenone was deduced by O'Malley and colleagues. RU486 or Mifepristone, a PR antagonist, demonstrated cell-line-specific agonist/antagonistic activities that resulted from the coactivator/corepressor ratio available in the respective cell lines (Liu et al., 2002). The same was also shown with tamoxifen, whose function was governed by the coactivator/corepressor ratio in breast cancer and uterine cell lines (Smith et al., 1997, Feng and O'Malley, 2014). Previously unreported data from our group supports the role of coactivators in the tissue-selective function of arylpropionamide SARMs (Fig. 2). Transactivation studies performed in C2C12 muscle cells and in prostate cancer PC3 cells in the presence of the coactivator SRC-1 indicate cell-type specific responses in AR-transactivation by DHT or SARM. This data suggests that the conformational change induced by the SARM facilitates the interaction of the AR with coactivators in muscle cell environments, while DHT-induced conformation facilitates the interaction of coactivators with the AR in the prostate cellular environment. We also evaluated the recruitment of the AR, coactivators, and corepressors to the androgen response elements (AREs) located on the PSA enhancer in LNCaP cells (Fig. 3). While DHT robustly recruited the coactivator SRC-1, but not corepressor NCoR, to the PSA enhancer, an arylpropionamide SARM recruited both SRC-1 and NCoR to the PSA enhancer. This suggests that the SARMs form a complex in the prostate cellular environment comprised of both coactivators and corepressors that will prevent maximal activation of the AR in this androgenic tissue. Alternatively, the SARMs and steroidal androgens utilize coactivators in anabolic tissues to promote maximal activation of the AR. These results and associated literature evidence are summarized in Fig. 4 as a model to demonstrate the role of coregulators in SARM action. Although this is a simplified version of the involvement of coregulators in SARMs function, we recognize the lack of overwhelming literature evidence for SARMs, unlike the SERMs. Differences in the transcriptional complex formed in response to ligand binding also modulate the rate of nuclear translocation and nuclear export. We identified that within the same structural scaffold, SARMs with minor structural modifications have completely distinct nuclear translocation potential, demonstrating that the conformational change induced by these SARMs has resulted in varying nuclear translocation rate (Narayanan et al., 2010).