Steroidal androgens and nonsteroidal, tissue-selective androgen receptor modulator, S-22, regulate androgen receptor function through distinct genomic and nongenomic signaling pathways.
Androgen receptor (AR) ligands are important for the development and function of several tissues and organs. However, the poor oral bioavailability, pharmacokinetic properties, and receptor cross-reactivity of testosterone, coupled with side effects, place limits on its clinical use. Selective AR modulators (SARMs) elicit anabolic effects in muscle and bone, sparing reproductive organs like the prostate. However, molecular mechanisms underlying the tissue selectivity remain ambiguous. We performed a variety of in vitro studies to compare and define the molecular mechanisms of an aryl propionamide SARM, S-22, as compared with dihydrotestosterone (DHT). Studies indicated that S-22 increased levator ani muscle weight but decreased the size of prostate in rats. Analysis of the upstream intracellular signaling events indicated that S-22 and DHT mediated their actions through distinct pathways. Modulation of these pathways altered the recruitment of AR and its cofactors to the PSA enhancer in a ligand-dependent fashion. In addition, S-22 induced Xenopus laevis oocyte maturation and rapid phosphorylation of several kinases, through pathways distinct from steroids. These studies reveal novel differences in the molecular mechanisms by which S-22, a nonsteroidal SARM, and DHT mediate their pharmacological effects.
Narayanan
Ramesh
R
Preclinical Research and Development, GTx, Inc., 3 North Dunlap Street, Memphis, Tennessee 38163, USA.
Coss
Christopher C
CC
Yepuru
Muralimohan
M
Kearbey
Jeffrey D
JD
Miller
Duane D
DD
Dalton
James T
JT
D000577:Amides / Q000494:pharmacology; D045930:Anabolic Agents / Q000494:pharmacology; D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D013196:Dihydrotestosterone / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D011944:Receptors, Androgen / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects; D014981:Xenopus; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000577:Amides; D045930:Anabolic Agents; D000726:Androgen Antagonists; D000728:Androgens; D017931:DNA Primers; D008024:Ligands; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D019950:Mitogen-Activated Protein Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C034666:propionamide