17 alpha-propionate is a new topical and peripherally selective androgen antagonist. 17 alpha-propionate (CB-03-01) is a new potent topical antiandrogen potentially useful in acne vulgaris. CB-03-01 1% cream was very well tolerated, and was significantly better than placebo regarding TLC (P = 0·0017), ILC (P = 0·0134) and ASI (P = 0·0090), and also clinically more effective than comparator. The product also induced a faster attainment of 50% improvement in all the above parameters.
ARN-509 is a selective and competitive androgen receptor inhibitor with IC50 of 16 nM, useful for prostate cancer treatment. IC50 value: 16 nM Target: androgen receptor
ARN-509 is an androgen receptor antagonist with potential antineoplastic activity. ARN-509 binds to AR in target tissues thereby preventing androgen-induced receptor activation and facilitating the formation of inactive complexes that cannot be translocated to the nucleus. This prevents binding to and transcription of AR-responsive genes. This ultimately inhibits the expression of genes that regulate prostate cancer cell proliferation and may lead to an inhibition of cell growth in AR-expressing tumor cells.
ASC-J9(GO-Y025; Dimethylcurcumin), is antitumor agent; ASC-J9 suppresses castration-resistant prostate cancer growth via degradation of full-length and splice variant androgen receptors. IC50 value: Target:
Research results suggested that targeting both fAR- and AR3-mediated PCa growth by ASC-J9 may represent the novel therapeutic approach to suppress castration-resistant PCa. ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor.
AZD3514 is a potent and oral androgen receptor downregulator with Ki of 2.2 μM and has ability of reducing AR protein expression. IC50 Value: 2.2 uM (Ki)
Target: androgen receptor
AZD3514 binds to the AR ligand binding domain and has selectivity for binding to AR over other nuclear hormone receptors . in vitro: AZD3514 inhibits cell growth in prostate cancer cells expressing wild-type (VCaP) and mutated (T877A) AR (LNCaP), but is inactive in AR-negative prostate cancer cells, indicating a dependency on AR for efficacy . in vivo: We assessed activity initially in the Hershberger castrated rat assay in which oral dosing of AZD3514 (100mg/kg once-daily for 7 days) significantly inhibited testosterone-induced growth of sexual accessory organs . Clinical trial: Open-label Prostate Cancer Study. Phase 1
Description: IC50 Value: 0.16uM. Bicalutamide is an oral non-steroidal anti-androgen for prostate cancer. It binds to the androgen receptor. Bicalutamide (BIC) is a drug of choice for the treatment of progressive androgen-dependent prostate cancer. in vitro: Bicalutamide treatment of LNCaP/AR(cs) cells in absence of the synthetic androgen R1881 resulted in altered gene-expression consistent with its well-documented agonist activity in context of AR over-expression. In absence of R1881, bicalutamide partially activated VP16-AR-mediated transcription, indicative of AR binding to DNA. In LNCaP/AR-luc cells with a stably integrated AR-driven luciferase reporter construct, bicalutamide was unable to activate wtAR. ARN-509 (IC50=16 nM) binds AR with 7- to 10-fold greater affinity than the clinically approved anti-androgen, bicalutamide (median IC50=160 nM), and competes for the same binding-site in the ligand-binding pocket of the receptor. in vivo: Ridaforolimus and bicalutamide combination treatment promotes cell cycle arrest in prostate cancer cells. The effect of combination treatment was more pronounced, resulting in an almost complete G1 arrest in this cell line. Clinical trail: Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer is reported in 2012.
IC50 Value: 2.11 ± 0.16 nM (Ki value)
BMS-564929 is a novel, highly potent, orally active, nonsteroidal tissue selective androgen receptor (AR) modulator, and this compound has been advanced to clinical trials for the treatment of age-related functional decline. BMS-564929 is a subnanomolar AR agonist in vitro, is highly selective for the AR vs. other steroid hormone receptors, and exhibits no significant interactions with SHBG or aromatase.
in vitro: BMS-564929 is a high affinity ligand for AR with a Ki of 2.11 ± 0.16 nM. This compound is more than 1000-fold selective for AR vs. ERα and β, GR, and MR, and approximately 400-fold selective vs. PR . BMS-564929 exhibited a potency (EC50, calculated as the concentration at which 50% of the maximum stimulatory effect of DHT is achieved) of 0.44 ± 0.03 nM compared with 2.81 ± 0.48 nM measured for T in the C2C12 myoblast cell line . Sample preparation based on solid-phase extraction and subsequent LC-MS/MS measurement allowed for detection limits of 1-20 ng/mL, intra- and interday precisions of between 2.4 and 13.2% and between 6.5 and 24.2%, respectively .
in vivo: The compound was administered across a wide dose range (1 μg to 1 mg/kg) for 8 wk in the same recovery schedule of administration as the 2-wk experiments. A dose-dependent increase in levator ani muscle and prostate wet weight was observed with BMS-564929 treatment, with ED50 values of 0.001 and 0.09 mg/kg for the levator ani and prostate, respectively 
Clinical trial: N/A
Cyproterone acetate is an androgen receptor (AR) antagonist with IC50 of 7.1 nM, as well as a weak progesterone receptor agonist with weak pro-gestational and glucocorticoid activity. Target: Androgen Receptor
Cyproterone acetate clearly shows antagonistic properties, while being a partial agonist also, showing agonism for the AR, with EC50 of 4.0 μM, at relatively high concentrations . In the presence of 10 nM Testosterone, low concentrations of Cyproterone acetate inhibits T-stimulated transcription of 3XHRE-LUC, but at higher concentrations, transcription is stimulated. LH levels in Cyproterone acetate-treated rats do not dip below pretreatment levels, although they does not increase as much in the rats treated with 3.2 mg Cyproterone acetate/kg/day as in those which received 0.2 mg Cyproterone acetate/kg/day . Cyproterone acetate exhibits direct negative effect on reproductive organs weight and significant reducing effect on sperm count and Ca2+ contents. SOD and GST activities significantly decrease in addition to significant increase in NO, MDA contents reflecting the oxidative status of testis in Cyproterone acetate treated rats .
Flutamide is an antiandrogen drug, with its active metablolite binding at androgen receptor with Ki values of 55 nM, and primarily used to treat prostate cancer. Target: androgen receptor in vitro: Flutamide (Eulexin) is an antiandrogen drug. Flutamide-OH, the active metabolite of flutamide, directly binds at rat anterior pituitary androgen receptor with Ki values of 55 nM . lutamide does not affect the proliferation of an androgen-sensitive clone of the mouse mammary carcinoma Shionogi SC-l 15 cells in culture, shows only antiandrogenic effect, but not androgenic effect . Flutamide provides treatment for prostate cancer when used along with leuprolide . in vivo: Flutamide causes a markedly reduction in rat ventral prostate weight from 319 mg to 245 mg. A combination of flutamide and LHRH agonist induces an additive effect with a decrease in prostate weight to 101 mg, and an marked drop in prostatic ODC activity .
IC50 Value: 6.6 nM 
MK-0773, one of Selective androgen receptor modulators (SARMs), is a 4-aza-steroid that exhibited tissue selectivity in humans.
in vitro: The IC50 of MK-0773 binding to AR was increased 3.5-fold in the presence of 25% rat serum and 13-fold in the presence of 25% human serum, indicating that it binds to serum proteins. The affinity of MK-0773 for AR across species was evaluated using COS cells transfected with AR, and IC50 values were very similar in four species (rat, 0.50 nM; dog, 0.55 nM; rhesus, 0.45 nM; human, 0.65 nM) .
in vivo: MK-0773 was dosed subcutaneously for 24 days in the OVX rat model (6 and 80 mg/kg) and produced plasma exposures over 24 h of 6.6 and 62 μM·h. This treatment produced exposure-related stimulatory effects on cortical BFR and LBM. The maximal anabolic effects of MK-0773 were equivalent to the SARM TFM-4AS-1 and ?80% of 3 mg/kg DHT . Participants receiving MK-0773 showed a statistically significant increase in LBM from baseline at Month 6 vs. placebo (p<0.001). Participants receiving both MK-0773 and placebo showed a statistically significant increase in strength from baseline to Month 6, but the mean difference between the two groups was not significant (p=0.269) .
Clinical trial: Safety, Tolerability and Efficacy of MK-0773 in Healthy Postmenopausal Women. Phase 1
N-desmethyl Enzalutamide(N-desmethyl MDV3100) is a major metabolite of Enzalutamide, Enzalutamide(MDV3100) is an androgen-receptor (AR) antagonist with IC50 of 36 nM. IC50 value: Target: androgen-receptor
Enzalutamide has greater affinity to AR than Bicalutamide does in a competition assay with 16β-[18F]fluoro-5α-DHT (18-FDHT) in castration-resistant LNCaP/AR cells (AR-overexpressing). While Enzalutamide shows no agonism in LNCaP/AR prostate cells. Enzalutamide antagonizes induction of prostate-specific antigen (PSA) and transmembrane serine protease 2 (TMPRSS2), combination with the synthetic androgen R1881 in parental LNCaP cells. Enzalutamide could inhibit the transcriptional activity of a mutant AR protein (W741C, mutation of Trp741 to Cys). Enzalutamide also prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. Enzalutamide induces great tumor regression in castrate male mice bearing LNCaP/AR xenografts at a dose of 10 mg/kg.
Ostarine (MK-2866) is an androgen receptor modulator (SARM) with an ED50 of 0.44 mg/day. Ostarine (MK-2866) has anabolic activity. Lack of PSA increases in men and hair growth in women further corroborated selective anabolic effects of Ostarine (MK-2866). Ostarine (MK-2866) also resulted in a dose-dependent decrease in LDL and HDL cholesterol levels, with the average LDL/HDL ratio for all doses remaining in the low cardiovascular risk catergory.
Oxandrolone(SC11585) is a synthetic hormone with anabolic and androgenic properties. Target: Androgen Receptor
Oxandrolone is a synthetic hormone with anabolic and androgenic properties. Studies with in vitro translated glucocorticoid receptor (GR), however, showed no inhibition of cortisol binding by oxandrolone. Conversely, experiments in cell culture systems demonstrated significant antagonism of cortisol-induced transcriptional activation by oxandrolone in cells expressing both the AR and GR. Inhibition was not overcome by increased cortisol concentration, and no inhibition by oxandrolone was observed in cells expressing GR alone, confirming that non-competitive mechanisms were involved. These data indicate a novel action of oxandrolone to suppress glucocorticoid action via crosstalk between AR and GR . Oxandrolone reduced total (-1.9 +/- 1.0 kg) and trunk fat (-1.3 +/- 0.6 kg; P < 0.001), and these decreases were greater (P < 0.001) than placebo. Thus oxandrolone induced short-term improvements in LBM, muscle area, and strength, while reducing whole body and trunk adiposity. Anabolic improvements were lost 12 wk after discontinuing oxandrolone, whereas improvements in fat mass were largely sustained . Oxandrolone administration is effective in promoting dose-dependent gains in body weight and BCM in HIV-infected men with weight loss .
Spironolactone is a potent antagonist of the androgen receptor. Target: Androgen Receptor
Spironolactone is a potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects. 5% topical spironolactone cream acts as an antiandrogen in human sebaceous glands, competing with DHT receptors and producing a decrease of labelled DHT. At the concentrations used the effect has been only local. No side-effects were recorded during both studies . Patients who received spironolactone had a significant improvement in the symptoms of heart failure, as assessed on the basis of the New York Heart Association functional class (P<0.001). Gynecomastia or breast pain was reported in 10 percent of men who were treated with spironolactone, as compared with 1 percent of men in the placebo group (P<0.001). The incidence of serious hyperkalemia was minimal in both groups of patients .
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and othervertebrates. IC50 Value: Target: Androgen Receptor in vitro: In rat aortic strips, 5-20 min treatment with physiological concentrations of testosterone significantly increased nitric oxide (NO) production. Testosterone modulates vascular EC growth and platelet aggregation through its direct action on endothelial NO production . in vivo: The mean age was 39 years, and the mean pretreatment testosterone and estrogen levels were 247.6 +/- 39.8 ng/dL and 32.3 +/- 10.9, respectively. By the first follow-up visit (4-6 weeks), the mean testosterone level rose to 610.0 +/- 178.6 ng/dL (P < 0.00001). Moreover, the T/E ratio improved from 8.7 to 14.2 (P < 0.001) . Serumtestosterone levels in three-quarter patients after surgical castration drop to less than 20ng/dl (0.69nmol/l). Ineffective suppression of testosterone is currently poorly recognized and may possibly have an effect of prostate cancer mortality . Clinical trial: Safety and Efficacy Trial of Oral Testosterone Undecanoate (TU) in Hypogonadal Men. Phase 3
Biological Activity of Enzalutamide
Enzalutamide (MDV3100) is an androgen-receptor (AR) antagonist with IC50 of 36 nM. IC50 value: 36 nM  Target: androgen-receptor in vitro: Enzalutamide has greater affinity to AR than Bicalutamide does in a competition assay with 16β-[18F]fluoro-5α-DHT (18-FDHT) in castration-resistant LNCaP/AR cells (AR-overexpressing). While Enzalutamide shows no agonism in LNCaP/AR prostate cells. Enzalutamide antagonizes induction of prostate-specific antigen (PSA) and transmembrane serine protease 2 (TMPRSS2), combination with the synthetic androgen R1881 in parental LNCaP cells. Enzalutamide could inhibit the transcriptional activity of a mutant AR protein (W741C, mutation of Trp741 to Cys) . Enzalutamide also prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex . in vivo: Enzalutamide induces great tumor regression in castrate male mice bearing LNCaP/AR xenografts at a dose of 10 mg/kg .
Clinical Information of Enzalutamide
Last Change Date
Astellas Pharma Global Development Inc
Hormone refractory prostate cancer
Phase 4 Clinical
Metastatic prostate cancer
Phase 2 Clinical
Medivation Inc; Novotech Clinical Research (M) Sdn. Bhd
Hormone refractory prostate cancer
Phase 3 Clinical
Hormone refractory prostate cancer
Phase 3 Clinical
Alliance for Clinical Trials in Oncology
Hormone refractory prostate cancer
Phase 3 Clinical
References on Enzalutamide
. Tran C, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science, 2009, 324 (5928), 787-790.
. Scher HI, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet, 2010, 375(9724), 1437-1446.
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