title: Mechanism of the tissue-specific action of the selective androgen receptor modulator S-101479.
abstract: Selective androgen receptor modulators (SARMs) comprise a new class of molecules that induce anabolic effects with fewer side effects than those of other anabolic agents. We previously reported that the novel SARM S-101479 had a tissue-selective bone anabolic effect with diminished side effects in female animals. However, the mechanism of its tissue selectivity is not well known. In this report, we show that S-101479 increased alkaline phosphatase activity and androgen receptor (AR) transcriptional activity in osteoblastic cell lines in the same manner as the natural androgen ligand dihydrotestosterone (DHT); conversely, stimulation of AR dimerization was very low compared with that of DHT (34.4%). S-101479 increased bone mineral content in ovariectomized rats without promoting endometrial proliferation. Yeast two-hybrid interaction assays revealed that DHT promoted recruitment of numerous cofactors to AR such as TIF2, SRC1, β-catenin, NCoA3, gelsolin and PROX1 in a dose-dependent manner. SARMs induced recruitment of fewer cofactors than DHT; in particular, S-101479 failed to induce recruitment of canonical p160 coactivators such as SRC1, TIF2 and notably NCoA3 but only stimulated binding of AR to gelsolin and PROX1. The results suggest that a full capability of the AR to dimerize and to effectively and unselectively recruit all canonical cofactors is not a prerequisite for transcriptional activity in osteoblastic cells and resulting anabolic effects in bone tissues. Instead, few relevant cofactors might be sufficient to promote AR activity in these tissues.
authors: Central Research Laboratories, Kaken Pharmaceutical Co., Ltd, 14 Shinomiya, Minamigawara-cho, Yamashina-ku, Kyoto 607–8042, Japan. furuya_kazuyuki@kaken.co.jp
authors: Kazuyuki
authors: K
authors: Furuya
authors: Noriko
authors: N
authors: Yamamoto
authors: Yuki
authors: Y
authors: Ohyabu
authors: Teruyuki
authors: T
authors: Morikyu
authors: Hirohide
authors: H
authors: Ishige
authors: Michael
authors: M
authors: Albers
authors: Yasuhisa
authors: Y
authors: Endo
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D005260:Female; D009928:Organ Specificity; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D010052:Ovariectomy; D055503:Protein Multimerization; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D015533:Transcriptional Activation
chemical_list: D001572:Benzofurans; C582954:N-(2-((3aS,4S,9bS)-8-cyano-1-formyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo(3,2-c) quinolin-4-yl)-2-methylpropyl)-4,6-difluorobenzofuran-2-carboxyamide; D011804:Quinolines; D011944:Receptors, Androgen; D013196:Dihydrotestosterone