A Novel Synthetic Androgen Receptor Ligand, S42, Works as a Selective Androgen Receptor Modulator and Possesses Metabolic Effects with Little Impact on the Prostate

Liu, Min; Yanase, Toshihiko; Tanaka, Tomoko; Fan, Wu; Nomura, Masatoshi; Kawate, Hisaya; Okabe, Taijiro; Takayanagi, Ryoichi; Nawata, Hajime

doi:10.1210/en.2009-0405

Cited by 16 publications

(12 citation statements)

References 51 publications

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“…Thus, there has been intense interest in the discovery of SARM, and several AR ligands with SARM-like properties have been reported. [29][30][31][32] YK11 acts as a gene-selective agonist of AR in MDA-MB 453 cells. This type of selective gene induction by AR has been observed when AR is liganded with selective AR modulators (SARMs), 31) a class of drugs that produce cell-specific anabolic effects in tissues such as bone and muscle without causing androgenic effects in other tissues such as those of reproduction.…”

Section: Discussionmentioning

confidence: 99%

(17.ALPHA.,20E)-17,20-[(1-Methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic Acid Methyl Ester (YK11) Is a Partial Agonist of the Androgen Receptor

Kanno

Hikosaka

Zhang

et al. 2011

Biological & Pharmaceutical Bulletin

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The androgen receptor (AR) is a member of the nuclear receptor (NR) superfamily of ligand-dependent transactivation factors. Androgens such as testosterone and 5-a-dihydrotestosterone (DHT) act as agonists of AR. AR mediates various biological effects such as the development of male reproductive tissues, sexual development, and spermatogenesis. [1][2][3][4] Since androgen declining with age contributes to age-related bone and muscle loss and increase in fat mass, 5) the anabolic effect of androgen is attractive for the maintenance of health. Furthermore, it is known that AR is involved in androgen-dependent prostate cancer growth. Thus, antagonists of AR (flutamide, bicalutamide, and nilutamide) are used in anti-androgen therapy for prostate cancer. 8,9) AR mediates the expression of androgen-regulated genes, as represented by prostate specific antigen (PSA) [10][11][12] and FK506-binding protein 51 (FKBP51). [13][14][15] In the absence of a ligand, AR is localized in the cytoplasm, where it forms complexes with chaperones. Upon ligand binding, AR translocates into the nucleus. Following nuclear translocation, AR binds to androgen responsive elements (ARE) in the promoter regions of its target genes as a homodimer. Generally, the transcriptional activity of nuclear receptors is modulated by their interaction with cofactors such as coactivators and corepressors. [16][17][18][19] The type of ligand that binds to the receptor determines which type of cofactor is chosen. In the case of agonists, AR interacts with coactivators dominantly over corepressors, and vice versa in the case of antagonists.Unlike other nuclear receptors, AR AF2 demonstrates weak transcriptional activity. However, ligand-dependent interaction between NTD and LBD/AF2 (which is termed as the N/C interaction) endows AR with synergistic transactivation potential. [20][21][22][23] Thus, the N/C interaction is important for the ligand-dependent transactivation potential of AR.Synthetic AR ligands are useful for treatment of prostate cancer and age-related diseases such as osteopenia and sarcopenia. Previously, we prepared novel synthetic steroids.24) In our preliminary screening for novel AR ligands, a steroid compound, (17a,20E)-17,20-[(1-methoxyethylidene) bis(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic acid methyl ester (YK11), behaved apparently as a partial agonist of AR in an ARE-luciferase reporter assay (unpublished data). We were interested in this partial agonistic nature of YK11. In this report, we will show that YK11 blocks the N/C-interaction required for the full-agonistic function of wild-type AR, inducing selective AR-target genes owing to the constitutive transactivation potential of AF-1 subdomain in endogenous AR-expressing MDA-MB 453 cells. MATERIALS AND METHODS ChemicalsThe compounds tested in our preliminary screening for novel AR ligands were prepared by previously

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Section: Discussionmentioning

confidence: 99%

(17.ALPHA.,20E)-17,20-[(1-Methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic Acid Methyl Ester (YK11) Is a Partial Agonist of the Androgen Receptor

Kanno

Hikosaka

Zhang

et al. 2011

Biological & Pharmaceutical Bulletin

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“…The development of selective androgen receptor-modulating therapies may help mitigate many of these side effects. Preclinical and phase II trials of candidate drugs have demonstrated beneficial effects on insulin sensitivity as well as on muscle mass and strength (Gao et al 2005, Dalton et al 2011, Min et al 2009). …”

Section: Additional Therapeutic Perspectivesmentioning

confidence: 99%

Insulin resistance and sarcopenia: mechanistic links between common co-morbidities

Cleasby

Jamieson

Atherton

2016

Journal of Endocrinology

409

296

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Insulin resistance (IR) in skeletal muscle is a key defect mediating the link between obesity and type 2 diabetes, a disease that typically affects people in later life. Sarcopenia (age-related loss of muscle mass and quality) is a risk factor for a number of frailty-related conditions that occur in the elderly. In addition, a syndrome of 'sarcopenic obesity' (SO) is now increasingly recognised, which is common in older people and is applied to individuals that simultaneously show obesity, IR and sarcopenia. Such individuals are at an increased risk of adverse health events compared with those who are obese or sarcopenic alone. However, there are no licenced treatments for sarcopenia or SO, the syndrome is poorly defined clinically and the mechanisms that might explain a common aetiology are not yet well characterised. In this review, we detail the nature and extent of the clinical syndrome, highlight some of the key physiological processes that are dysregulated and discuss some candidate molecular pathways that could be implicated in both metabolic and anabolic defects in skeletal muscle, with an eye towards future therapeutic options. In particular, the potential roles of Akt/mammalian target of rapamycin signalling, AMP-activated protein kinase, myostatin, urocortins and vitamin D are discussed. R67-R81 229:2 Muscle insulin resistance and sarcopenia Associations between obesity, diabetes and skeletal muscle ageingThe International Diabetes Federation has estimated that there were 382 million people living with diabetes in 2013, with this number predicted to rise to 592 million by 2035, of which the significant majority would be of >40 years old (IDF 2013). Of these, 90% suffer from type 2 diabetes (T2D), which is characterised by both β-cell failure and resistance to the actions of insulin at the tissue level (insulin resistance, IR). As skeletal muscle is responsible for the majority of the body's postprandial glucose disposal, IR in this tissue results in substantial whole-body metabolic disturbances. However, it is likely that the metabolic disturbances associated with T2D are further exacerbated by the marked loss of skeletal muscle mass that can also be associated with these conditions (Park et al. 2009, Kim et al. 2010. Specifically, loss of muscle mass induces a 2-3% decline in basal metabolic rate per decade after the age of 20 years and 4% per decade after the age of 50 years, resulting from concomitant loss of mitochondrial volume density and oxidative capacity (Conley et al. 2000). Journal of EndocrinologyThis loss of muscle mass in the elderly is also the principal factor responsible for 'frailty', a syndrome that has been clinically defined as the possession of three of: unintentional weight loss (10 pounds (~4.5 kg) in the past year), self-reported exhaustion, weakness (poor grip strength), slow walking speed and low physical activity (Fried et al. 2001). Loss of muscle mass (atrophy) is an inevitable, although somewhat modifiable, process that occurs with ageing (Sayer et al. 2008), w...

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“…Furthermore, administration of S42 to orchiectomized Sprague–Dawley rats for 3 weeks was as effective as DHT in increasing the weight of the levator ani muscle, but did not elevate the prostate weight at any dose, in contrast to the effect of DHT. These results suggest that, while sparing the prostate from potentially harmful effects, S42 had an anabolic action in orchiectomized rats [10] .…”

Section: Introductionmentioning

confidence: 74%

“…In an effort to develop a SARM with beneficial activity in energy homeostasis, we previously screened 119 steroid analogs for the ability to induce uncoupling protein-1 mRNA without increasing prostate-specific antigen promoter activity in the human PC cell line, LNCaP [10] . As a result, we identified a novel SARM, S42, which is a structural analog of testosterone [10] . In LNCaP cells, S42 does not induce AR transactivation, but antagonizes 5α-dihydrotestosterone (DHT)-induced AR activation [10] .…”

Section: Introductionmentioning

confidence: 99%

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Selective androgen receptor modulator, S42 has anabolic and anti-catabolic effects on cultured myotubes

Muta

Tanaka

Hamaguchi

et al. 2019

Biochemistry and Biophysics Reports

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We previously identified a novel selective androgen receptor modulator, S42, that does not stimulate prostate growth but has a beneficial effect on lipid metabolism. S42 also increased muscle weight of the levator ani in orchiectomized Sprague–Dawley rats. These findings prompted us to investigate whether S42 has a direct effect on cultured C2C12 myotubes. S42 significantly lowered expression levels of the skeletal muscle ubiquitin ligase (muscle atrophy-related gene), atrogin1 and Muscle RING-Finger Protein 1(MuRF1) in C2C12 myotubes, as determined by real time PCR. Phosphorylation of p70 S6 kinase (p70S6K), an essential factor for promoting protein synthesis in skeletal muscle, was significantly increased by S42 to almost the same extent as by insulin, but this was significantly prevented by treatment with rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1). However, phosphorylation of Akt, upstream regulator of mTORC1, was not changed by S42. S42 did not increase insulin-like growth factor 1 (Igf1) mRNA levels in C2C12 myotubes. These results suggest that S42 may have an anabolic effect through activation of mTORC1–p70S6K signaling, independent of IGF-1-Akt signaling and may exert an anti-catabolic effect through inhibition of the degradation pathway in cultured C2C12 myotubes.

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A Novel Synthetic Androgen Receptor Ligand, S42, Works as a Selective Androgen Receptor Modulator and Possesses Metabolic Effects with Little Impact on the Prostate

Cited by 16 publications

References 51 publications

(17.ALPHA.,20E)-17,20-[(1-Methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic Acid Methyl Ester (YK11) Is a Partial Agonist of the Androgen Receptor

(17.ALPHA.,20E)-17,20-[(1-Methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic Acid Methyl Ester (YK11) Is a Partial Agonist of the Androgen Receptor

Insulin resistance and sarcopenia: mechanistic links between common co-morbidities

Selective androgen receptor modulator, S42 has anabolic and anti-catabolic effects on cultured myotubes

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