Identification of an anabolic selective androgen receptor modulator that actively induces death of androgen-independent prostate cancer cells

Schmidt, Azriel; Meißner, Robert; Gentile, Michael A.; Chisamore, Michael; Opas, Evan E.; Scafonas, Angela; Cusick, T.; Gambone, Carlo J.; Pennypacker, Brenda L; Hodor, Paul; Perkins, James J.; Bai, Chang; Ferraro, Damien; Bettoun, David; Wilkinson, Hilary A.; Alves, Stephen E.; Flores, Osvaldo; Ray, William J.

doi:10.1016/j.jsbmb.2014.02.005

Cited by 16 publications

(12 citation statements)

References 54 publications

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“…The amino (NH 2 ) and carboxy (COOH) termini of the AR can bind to one another in the presence of ligand and this may influence AR activity, termed N‐C interactions [Langley et al, ]. Previous publications have correlated the N‐C interactions to androgenic activity of an AR ligand [Schmidt et al, , ]. To examine the effects of SARMs on the interactions of the NH 2 and COOH termini of the AR, a cell model was utilized that contains constructs designed to measure the ability of the compounds to induce this interaction.…”

Section: Resultsmentioning

confidence: 99%

Tissue Selective Androgen Receptor Modulators (SARMs) Increase Pelvic Floor Muscle Mass in Ovariectomized Mice

et al. 2016

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Stress urinary incontinence (SUI), a prevalent condition, is represented by an involuntary leakage of urine that results, at least in part, from weakened or damaged pelvic floor muscles and is triggered by physical stress. Current treatment options are limited with no oral therapies available. The pelvic floor is rich in androgen receptor and molecules with anabolic activity including selective androgen receptor modulators (SARMs) may serve as therapeutic options for individuals with SUI. In this study, two SARMs (GTx-024 and GTx-027) were evaluated in a postmenopausal animal model in order to determine their effect on pelvic floor muscles. Female C57BL/6 mice were ovariectomized and their pelvic muscles allowed to regress. The animals were then treated with vehicle or doses of GTx-024 or GTx-027. Animal total body weight, lean body mass, and pelvic floor muscle weights were measured along with the expression of genes associated with muscle catabolism. Treatment with the SARMs resulted in a restoration of the pelvic muscles to the sham-operated weight. Coordinately, the induction of genes associated with muscle catabolism was inhibited. Although a trend was observed towards an increase in total lean body mass in the SARM-treated groups, no significant differences were detected. Treatment of an ovariectomized mouse model with SARMs resulted in an increase in pelvic floor muscles, which may translate to an improvement of symptoms associated with SUI and serves as the basis for evaluating their clinical use. J. Cell. have bladder muscles that can squeeze too often and/or without warning. The dysfunctional bladder will result in a spectrum of symptoms which vary in severity and type. These include increases in urinary frequency and urgency. Accompanying the urgency can be urge urinary incontinence in which the elevated urge results in an involuntary leakage of urine. OAB and its associated symptoms are known to affect more than 33 million people in the United States but estimates have been made that 30% of men and 40% of women live with OAB symptoms with the prevalence increasing with age [FDA, 2015]. The causes of OAB have been mainly attributable to neurological conditions but the broad range of associated symptoms have been linked to other conditions such as urinary tract infections, prostatitis or benign prostatic hyperplasia, and pregnancy [Homma, 2014].As opposed to OAB, in which the bladder muscles are "overactive," stress urinary incontinence (SUI) is a condition in which the pelvic muscles and tissues that support the bladder and urethra have become weak, which can permit the bladder neck to descend during busts of physical activity that increase abdominal pressure including coughing, sneezing, laughing, or exercise. Another cause of SUI, is a weakened sphincter muscle that controls the urethra. SUI occurs predominantly in women and the weakened

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Section: Resultsmentioning

confidence: 99%

Tissue Selective Androgen Receptor Modulators (SARMs) Increase Pelvic Floor Muscle Mass in Ovariectomized Mice

et al. 2016

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“…10 Although the detailed mechanism is not fully clear, it is well accepted that an idea SARM should behave like natural androgen in muscle and bone, and lead to only minimal benign hyperplasia or even play a role of AR antagonist in prostate. However, the opinion of Schmidt et al 152 by biological experiments established to distinguish AR antagonists in PCa therapy, and then further verified by its anabolic activity. 152,156 As a carborane compound, BA321 is supposed to interact with hormone receptors.…”

Section: Ar and Anabolic Deficienciesmentioning

confidence: 97%

“…However, the opinion of Schmidt et al 152 by biological experiments established to distinguish AR antagonists in PCa therapy, and then further verified by its anabolic activity. 152,156 As a carborane compound, BA321 is supposed to interact with hormone receptors. It was chemically synthesized and biologically evaluated for its SARM activity.…”

Section: Ar and Anabolic Deficienciesmentioning

confidence: 97%

“…Although the detailed mechanism is not fully clear, it is well accepted that an idea SARM should behave like natural androgen in muscle and bone, and lead to only minimal benign hyperplasia or even play a role of AR antagonist in prostate. However, the opinion of Schmidt et al is that blocking all AR activities by SARM is not aspired in PCa, because some other AR regulated gene in prostate are perhaps still desirable to express. In literatures, a group of nonsteroidal SARMs (eg, RAD140 [ 36 ], MK‐4541 [ 37 ], and BA321 [ 38 ]) have been reported.…”

Section: Ar and Anabolic Deficienciesmentioning

confidence: 99%

“…The lead compound was formerly discovered by a series of assays such as oral activity, in vivo activity, synthetic intermediate testing, literature evaluation, and fragment combination . MK‐4541 was screened out from 3000 manually designed SARMs by biological experiments established to distinguish AR antagonists in PCa therapy, and then further verified by its anabolic activity . As a carborane compound, BA321 is supposed to interact with hormone receptors.…”

Section: Ar and Anabolic Deficienciesmentioning

confidence: 99%

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A magic drug target: Androgen receptor

Zhou

Pang

et al. 2018

Medicinal Research Reviews

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Androgen receptor (AR) is closely associated with a group of hormone‐related diseases including the cancers of prostate, breast, ovary, pancreas, etc and anabolic deficiencies such as muscle atrophy and osteoporosis. Depending on the specific type and stage of the diseases, AR ligands including not only antagonists but also agonists and modulators are considered as potential therapeutics, which makes AR an extremely interesting drug target. Here, we at first review the current understandings on the structural characteristics of AR, and then address why and how AR is investigated as a drug target for the relevant diseases and summarize the representative antagonists and agonists targeting five prospective small molecule binding sites at AR, including ligand‐binding pocket, activation function‐2 site, binding function‐3 site, DNA‐binding domain, and N‐terminal domain, providing recent insights from a target and drug development view. Further comprehensive studies on AR and AR ligands would bring fruitful information and push the therapy of AR relevant diseases forward.

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Modulation of the Androgen Receptor Axis

Mohler

Dalton

2021

Burger's Medicinal Chemistry and Drug Discovery

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The androgen receptor (AR) mediates the endocrine functions of endogenous androgens like testosterone and exerts pleiotropic androgenic (male phenotype development, sexual function) and anabolic (growth and maintenance of musculoskeletal system) effects across most tissues. The AR‐axis, i.e. AR and its downstream effects, is extensively targeted to stimulate anabolism or treat prostatic diseases. Tissue‐selective, direct‐acting synthetic AR agonists are limited in scope by their inadequate separation of anabolic from untoward androgenic or virilizing effects and include FDA approved steroidal androgens (anabolic‐androgenic steroids) and investigational nonsteroidal selective AR modulators (SARMs). Gaining in popularity is testosterone replacement therapy in hypogonadal men. Antagonism of the AR‐axis is common in aging males with androgen‐dependent prostate hyperproliferation [prostate cancer or benign prostatic hyperplasia (BPH)]. Androgen ablation (indirect antagonism) and direct AR antagonism have been the mainstays of prostate cancer therapies for many decades including recent approvals. Indirect antagonists of the AR‐axis include gonadotropin‐releasing hormone agonists or antagonists (androgen‐deprivation therapy), which achieve systemic androgen and estrogen ablation for prostate or breast cancers as a monotherapy or sometimes in combination with steroidogenic enzyme (lyase) inhibitors. DHT‐dependent diseases are treated with 5α‐reductase to block intracrine production of DHT for male pattern baldness and BPH; whereas aromatase inhibitors block androgen metabolism to estrogen in breast cancer. Direct AR antagonists (antiandrogens) with improved potency and anti‐androgenic scope continue to be approved for prostate cancer. Research into innovative ways to directly or indirectly modulate the AR‐axis remains robust, suggesting new therapies will likely be introduced regularly for the foreseeable future.

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Identification of an anabolic selective androgen receptor modulator that actively induces death of androgen-independent prostate cancer cells

Cited by 16 publications

References 54 publications

Tissue Selective Androgen Receptor Modulators (SARMs) Increase Pelvic Floor Muscle Mass in Ovariectomized Mice

Tissue Selective Androgen Receptor Modulators (SARMs) Increase Pelvic Floor Muscle Mass in Ovariectomized Mice

A magic drug target: Androgen receptor

Modulation of the Androgen Receptor Axis

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