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.

Human in vivo metabolism study of LGD‐4033

“…15 • SARMs with tetrahydroquinolinone core structure, such as S-40503, 15 S-101479, 21 and S-49288. 22 • SARMs with indole core structure, such as RAD35010 15 and Ly2452473. 21 • SARMs with steroidal core structure, such as MK-0773, 15,23 Cl-4-AS-1, TMF-4AS-1, YK-11, and S-42.…”

Reconfiguring the AR-TIF2 Protein–Protein Interaction HCS Assay in Prostate Cancer Cells and Characterizing the Hits from a LOPAC Screen

“…7,14,32,35,37 SERMs and SARMS have convincingly demonstrated that small molecules can elicit tissue-or gene-selective effects, and recently, several groups have developed inhibitors that disrupt interactions between NRs and coactivator proteins. 7,14,31,32,35,37,38 For example, the bone-specific actions of the SARM S-101479 are the result of its failure to recruit TIF2, SRC-1, and NCoA3. 38 We have previously described an AR-TIF2 PPI biosensor (PPIB) HCS assay that can be used to screen for compounds that can induce, inhibit the formation of, or disrupt preexisting PPIs between AR and TIF2.…”

“…7,14,31,32,35,37,38 For example, the bone-specific actions of the SARM S-101479 are the result of its failure to recruit TIF2, SRC-1, and NCoA3. 38 We have previously described an AR-TIF2 PPI biosensor (PPIB) HCS assay that can be used to screen for compounds that can induce, inhibit the formation of, or disrupt preexisting PPIs between AR and TIF2. 20 However, the previous AR-TIF2 PPIB studies were conducted in the U-2 OS osteosarcoma cell line, and we wanted to determine whether the assay might perform differently when performed in a CaP cell background and whether AR-TIF2 PPI inhibitor or disruptor hits would behave differently.…”

Selective Androgen Receptor Modulator, YK11, Regulates Myogenic Differentiation of C2C12 Myoblasts by Follistatin Expression

“…A recent report has demonstrated that the SARM, S-101479, which shows low N/C interaction, induced recruitment of fewer cofactors than DHT. 34) This observation suggests that the difference in Fst mRNA regulation between YK11 and DHT stems from cofactor recruitment differences.…”