RAD140 is an orally available, non-steroidal SARM that is the subject of ongoing preclinical and clinical studies, and it continues to generate excitement across numerous scientific fields. It binds to and activates the androgen receptor (AR), and it shows a particularly desirable pattern of tissue-selective pharmacology, ie. high anabolic yet limited androgenic activity. This exceptional selectivity is being explored for use in metabolic conditions and cancer treatment applications.
Superior alternative to testosterone replacement therapy (TRT) , 
Treating breast cancer –
Selected RAD 140 Preclinical Data
“Design, Synthesis, and Preclinical Characterization of the Selective Androgen Receptor Modulator (SARM) RAD140” 
The androgen receptor (AR) is a member of the steroid hormone nuclear receptor superfamily that includes estrogen, progestin, and glucocorticoid receptors. The binding of the prototypical, body-produced androgen testosterone and the important active metabolite dihydrotestosterone (DHT) to AR initiates a remarkably diverse array of biological activities that can vary according to a subject’s sex, age and hormonal status. The activity of AR is critical to normal human sexual development and function, but beyond this signature role, AR activation also has important effects on diverse targets such as bone, liver, muscle and the central nervous system . The therapeutic potential of androgen signaling is well-appreciated in the medicinal chemistry community and chemists have long sought compounds that selectively stimulate muscle and bone growth while minimizing the proliferative effects on sex tissues such as the prostate in males. Such compounds have been termed selective androgen receptor modulators or SARMs. In this regard, the prototypical and endogenous androgen, testosterone, is considered to be a logical benchmark comparator. The stability of RAD140 was high in incubations with rat, monkey, and human microsomes, and it also had good bioavailability in rats (27−63%) and monkeys (65−75%). RAD140 demonstrated excellent affinity for the androgen as well as good selectivity over other steroid hormone nuclear receptors. In vitro functional androgen activator activity was confirmed in the bone cell differentiation assay.
Fig. 1. Tissue-selective activity of RAD140. The muscle (levator ani LABC), seminal vesicles (SV), and prostate weights from castrated immature rats treated for 11 days are plotted as a percent of testosterone propionate (TP) together with the standard deviation.
Fig. 2. Tissue-selective activity of RAD140 in young intact male rats. The muscle (levator ani LABC) and prostate weights from animals treated for 11 days are plotted with sham and vehicle controls. TP is testosterone propionate dosed subcutaneously daily in corn oil.
Fig. 3. Primate body weight from day −21, through 28 days dosing and 21 days post-dosing with RAD140 (0.01, 0.1, and 1 mg/kg. The change in baseline subtracted body weight from day −1 to day 29 was statistically significant for the 0.1 mg/kg and 1.0 mg/kg groups only. The change in body weight at day 29 between the 0.1 mg/kg group and the 0.01 mg/kg group was statistically significant as well.
RAD 140 Discussion
In this study, RAD140 was characterized in a number of in vivo assays to determine its oral efficacy on a number of parameters associated with androgenic activity in preclinical models. For example, RAD140 was dosed in both young castrated and intact male rats in order to assess its effects through a range of endogenous androgenic signaling backgrounds. The young castrated rat provides a very sensitive in vivo assay for androgenic activity because the animal is relatively androgen-naïve; thus, any signaling activity from an exogenously administered androgen is superimposed on an essentially blank background. The effect of increasing doses of orally administered RAD140 on levator ani bulbocavernosus muscle (“levator ani” or “LABC”) weight and prostate weight is shown relative to vehicle (castrated control), sham (noncastrated control), and testosterone propionate (TP). As can be seen, RAD140 stimulates the levator ani muscle beginning at a dose of 0.03 mg/kg and reaches a level of efficacy equivalent to the sham-operated animal at 0.3 mg/kg.
The goal of most preclinical, in vivo models is to best predict how a drug will perform in the drug target population. When considering the issue of how stimulatory an androgen is on any given tissue in a preclinical model, it is crucial that the background level of androgen signaling can affect the response observed in any animal. Thus, the castrated rat model has limitations because the very low endogenous androgen level in this model is an artificial situation, not reflected in the target adult human male population. In particular, the target male population will have an androgenic background well above a castrated individual, although the androgen levels will likely be lower than normal for their group. To better understand how this group might respond, the authors examined young intact male rats, since they have endogenous testosterone but at somewhat reduced levels. Therefore, they retain prostate sensitivity to an androgenic compound but at the same time have a baseline stimulation that is more similar to the target population than castrated animals. RAD140 increased the weight of the levator ani muscle above that of the intact control even with the lowest tested dose. Interestingly, RAD140 demonstrated no stimulation of the prostate above the intact animal control level until the highest dose tested. RAD140 demonstrated muscle efficacy similar to testosterone. From this study it is apparent that in young intact male rats RAD140 has a very wide range of preferred target-tissue selectivity relative to both testosterone-treated rats as well as sham-control rats.
Lastly, the authors sought to evaluate the effect of RAD140 in young, male cynomolgus monkeys to establish efficacious dosing levels in what we considered to be a more relevant preclinical species. They performed a simple study that still allowed the realistic evaluation of anabolic as well as lipids and other clinical chemistry parameters. To assess anabolic activity, they measured gross body weight, which is a sensitive marker of anabolic androgen action in young nonhuman primates such as monkeys. RAD140 was successful in promoting anabolic activities in primates.
Clinical chemistry indicated the expected lowering of lipids (LDL, HDL, and triglycerides). Despite the rather dramatic increases in body weight over such a short time, there was no elevation of liver enzyme transaminase levels in any animal at any dose >2 fold over its baseline value. Given the well-established relationship between oral androgen use and liver stress indicators, it was surprising that even at a dose 10-fold greater than the fully effective dose the authors observed only minimal liver enzyme elevations. Taken together, RAD140 has all the hallmarks of an exceptional SARM. It is potency selective, since it stimulates muscle weight increases at a lower dose than that required to stimulate prostate weight increases. Moreover, it is also efficacy selective, because it is fully anabolic on muscle but demonstrates less than complete efficacy on the prostate and seminal vesicles and, in fact, can partially antagonize the stimulation of the seminal vesicles induced by testosterone. RAD140 has excellent pharmacokinetics and is a potent anabolic in nonhuman primates as well. The overall preclinical profile of RAD140 is very good, and the compound has completed preclinical toxicology in both rats and monkeys. The next step for RAD140 for phase I clinical studies is to study it in patients suffering from severe weight loss due to cancer cachexia.
“Selective Androgen Receptor Modulator RAD140 Is Neuroprotective in Cultured Neurons and Kainate-Lesioned Male Rats” 
The decline in testosterone levels in men during normal aging increases risks of dysfunction and disease in androgen-responsive tissues, including the brain. The use of testosterone replacement therapy (TRT) has the potential to increase the risks for developing prostate cancer and or accelerating its progression. To overcome this limitation, novel compounds termed "selective androgen receptor modulators" (SARMs) have been developed that lack significant androgen action in prostate but exert agonist effects in select androgen-responsive tissues. The efficacy of SARMs in brain is largely unknown. In this study, the authors investigated RAD140 in cultured rat neurons and male rat brain for its ability to provide neuroprotection, an important neural action of body-produced androgens that is relevant to neural health and resilience to neurodegenerative diseases. In cultured hippocampal neurons, RAD140 was as effective as testosterone in reducing cell death induced by apoptotic insults. Importantly, RAD140 was also neuroprotective in vivo using the rat kainate lesion model. In experiments with gonadectomized, adult male rats, RAD140 was shown to exhibit peripheral tissue-specific androgen action that largely spared prostate and neuroprotection of hippocampal neurons against cell death caused by systemic administration of the toxin kainate. These novel findings demonstrate initial preclinical efficacy of a RAD140 in neuroprotective actions relevant to Alzheimer's disease and related neurodegenerative diseases.
Fig. 4. RAD140 increases neuron survival against plaques in a concentration-dependent manner. Neuron survival was measured in cultures pretreated with Testosterone (A) and DHT (B) RAD140 (C) and RAD192 (D) for 1 hour, followed by 24-hour exposure to plaque proteins (solid bars). Cell survival data show the average cell counts of viable cells expressed as percentage of vehicle-treated control group (white bars).
Fig. 5. RAD140 induces tissue-specific androgenic effects. Data show average tissue weights of (A) seminal vesicles, (B) prostate, and (C) levator ani muscle from male rats in sham-GDX (open bar), GDX (solid bar), GDX+T (gray bar), and GDX+RAD140 (gray bar) conditions. D, Relative mRNA levels of ERα in the hypothalamus were determined across groups by real-time PCR. Data show expression relative to the sham condition. GDX= gonadectomized, i.e. balls chopped off.
Fig. 6. Kainate (toxin) induced seizures and behavioral features of kainate-induced seizures were monitored and quantified for a 3-hour period following the brain lesion. Data show average values of (A) latency to seizure onset and (B) seizure severity across groups.
Additional RAD 140 Discussion
This study is the first to report findings of neuroprotective actions by SARMs in both cell culture and in vivo. These results show in primary neuron cultures in vitro that the SARM RAD140 increases cell viability against plaque toxicity in a concentration-dependent manner. The neuroprotective effects of RAD140 are specific to death-promoting insults. In gonadectomized (GDX) rats that were castrated, RAD140 induces androgenic responses in muscle and brain, but not in reproductive tissues. Moreover, RAD140 treatment significantly protected hippocampal neurons from kainite toxin lesions.
The promise of selective androgen treatment has been realized in animal models, with SARMs shown to promote muscle and bone health in the absence of prostate growth. These advances have encouraged evaluation of SARMs in clinical trials for disorders including cancer-induced muscle wasting and osteoporosis The data presented here are the first highlighting the potential efficacy of SARMs for brain health and defense. The fact that RAD140 can exert androgenic actions in brain at a dose that retains peripheral tissue selectivity is consistent with prior observations in rodents that the SARMs can prevent cognitive deficits.
The loss of androgens with normal aging can negatively impact androgen-responsive tissues, including the brain, and has been shown to be a significant risk factor for development of neurodegenerative disorders including Alzheimer’s disease. The increased risk for prostate cancer makes testosterone therapy a risky treatment option. Moreover, even in neurons, high doses of testosterone can be harmful rather than beneficial. In this regard, SARMs like RAD140 are clearly better alternatives to testosterone because they are only partial agonists or antagonists to androgenic regulation of prostate while still having androgenic effects on other tissues such as muscle and brain. In addition, higher doses of SARMs as compared with T might still promote neuron survival and not induce death, making them a suitable therapeutic strategy against age-related disorders such as Alzheimer’s disease.
“Selective Androgen Receptor Modulator RAD140 Inhibits the Growth of Androgen/Estrogen Receptor-Positive Breast Cancer Models with a Distinct Mechanism of Action” 
Steroidal androgens suppress androgen receptor and estrogen receptor positive (AR/ER+) breast cancer cells and were used to treat breast cancer, eliciting favorable response. This study evaluates the activity and efficacy of the oral selective AR modulator RAD140 using in vivo and in vitro models of AR/ER+ breast cancer. A series of in vitro assays were used to determine the affinity of RAD140 to 4 nuclear receptors and evaluate its tissue-selective AR activity. The efficacy and pharmacodynamics of RAD140 as monotherapy or in combination with palbociclib were evaluated in AR/ER+ breast cancer xenograft models. RAD140 bound AR with high affinity and specificity and activated AR in breast cancer but not prostate cancer cells. Oral administration of RAD140 substantially inhibited the growth of AR/ER+ breast cancer patient-derived xenografts (PDX).
Fig. 7. The effect of oral administration of RAD140 on the growth of AR/ER+ breast cancer PDX. Average tumor volumes of HBCx-22 breast cancer tumor xenografts treated with vehicle, RAD140, or fulvestrant for the indicated period of time (n = 8/group).
Fig. 8. Combined administration of RAD140 with a targeted inhibitor (palbociclib) reduced AR/ER+ patient-derived xenograft tumor growth. (A) Average tumor volumes of HBCx-3 breast cancer xenograft tumors treated with vehicle, RAD140, palbociclib, or a combination of RAD140 and palbociclib for the indicated period of time. (B) Average tumor volumes of ST897 breast cancer xenografts treated with vehicle, RAD140, palbociclib, or a combination of RAD140 and palbociclib for the indicated period of time.
RAD 140 Treatment of Breast Cancer Discussion
This study demonstrates for the first time that RAD140, an orally available SARM, is an AR agonist in breast cancer cells and suppresses the growth and proliferation of multiple breast cancer cell line and xenograft tumor models. The AR pathway was found to be activated in RAD140-treated breast cancer cells and xenografts. In addition, RAD140 treatment was found to decrease the expression of DNA replication–related genes in breast cancer cells, consistent with previous report that these genes were suppressed in androgen-treated prostate cancer cells. Combined administration of RAD140 with the targeted inhibitor palbociclib was more efficacious compared with either of the agents used alone. These findings suggest a distinct mechanism of action of RAD140 in inhibiting AR/ER+ breast cancer growth.
Accumulating evidence in the recent years has further defined the role of AR in breast cancer and has led to renewed interests in evaluating AR-targeted agents for breast cancer. Clinical benefit rates as high as 39% seen with androgen therapy in breast cancer patients experiencing disease progressing  along with prior experience with steroidal androgens in breast cancer together lend support to the development of a new generation of oral, nonsteroidal AR agonists for the treatment of AR/ER+ breast cancer.
SARMs may offer a novel approach to inhibit the growth of AR/ER+ breast cancers, with substantially reduced side effects commonly seen with classic non-selective androgens such as testosterone. The activity of RAD140 are AR specific, as evidenced by the similar effects observed with DHT and RAD140 on AR and its downstream targets, along with the reversal of these effects by AR antagonists. In addition, due to its nonsteroidal structure, the SARM RAD140 is not subject to further conversion to estrogens by aromatase, or to DHT by 5α-reductase, thus reducing the potential risk of stimulating ER+ tumor growth. As a proof-of-concept study, this study demonstrates that RAD140 treatment inhibited the growth of the breast cancer xenograft models supplemented by exogenous estrogen. Of note, RAD140 and its classic androgen comparator, DHT, also inhibited the proliferation of an endocrine-resistant breast cancer cell line model, HCC1428, suggesting AR agonists may inhibit the growth of ER+ breast cancer models with or without estrogen supplementation. Furthermore, in multiple patient derived tumor models, RAD140 inhibited tumor growth as a single agent, and this effect was enhanced by combining with palbociclib, which is now standard of care in treating certain kinds of breast cancer . Also, the growth pattern and response to RAD140 seen with HBCx-3 and HBCx-22 patient derived models, each evaluated in two independent studies, seemed to be consistent. This suggests good reproducibility of these studies.Therefore, the efficacy seen with RAD140 in these models may be suggestive of the potential therapeutic benefit in breast cancer patient population. As summarized elsewhere, AR agonists such as RAD140 exhibit inhibitory effect on AR/ER+ breast cells but not on AR+/ER− cells. It is conceivable that the varying degree of growth inhibition seen with SARM may be attributed to different ER positivity of these models.
The tissue selectivity of RAD140 is evidenced by potent androgen-like effects in bone and muscle, with much attenuated effects in other androgen-responsive tissues, such as prostate and seminal vesicles. Notably, when administered along with testosterone, RAD140 was found to partially antagonize the growth effect of testosterone in prostate and seminal vesicles, suggesting that RAD140 acts as a competitive AR ligand with attenuated activity. Here, the authors demonstrated for the first time that the SARM RAD140 is a potent AR activator in breast cancer cells. It exhibited attenuated activity on AR in prostate cancer cells, a finding consistent with the previously described attenuated effect on prostate growth. It has been proposed that the tissue-selective AR activity of SARMs is due to the differential activation of AR compared with classic androgens like testosterone, which impacts the recruitment of coactivators needed for AR-mediated activation. It is conceivable that AR upon binding to RAD140 assumes a shape change that only allows the interaction with a subset of coregulators that are uniquely expressed in breast epithelial cells.
Despite the preclinical evidence and favorable clinical outcome seen with androgens in ER+ breast cancer , improved understanding of the underlying mechanism is needed to further improve the design and development of new AR agonist-based therapy. It has been proposed that activated AR suppresses ER signaling by competing with ER for transcriptional coactivators or directly competing for binding sites and subsequently leads to inhibited cell proliferation suggesting a functional interference between these two nuclear receptors. Here, we show AR agonists, including RAD140 and DHT, activate AR target genes in breast cancer cells in vitro and in vivo, while suppressing a subset of ER target genes. Importantly, the authors found that treatment with RAD140 also led to substantial suppression of estrogen receptor. This may translate into unique therapeutic benefit of SARMs in overcoming resistance to estrogen receptor-targeted therapy seen in tumors with reactivated ER signaling. The inhibitory effect of RAD140 on the proliferation of HCC1428 breast cancer cells shed light on its efficacy in such estrogen-independent models, but further studies are needed to fully evaluate the activity of SARMs in similar models in vivo. In the current study, the RAD140-mediated suppression of estrogen signaling and its downstream pathways, along with the suppression of DNA replication and cell cycle–related genes suggest a distinct mechanism of action of this SARM in AR/ER+ breast cancer cells. The potent antitumor activity and tissue-selective AR activity, along with overall tolerability in animal models and oral availability together lend support to further clinical investigation of RAD140 in AR/ER+ breast cancer patients.
OVERALL CONCLUSION FOR RAD 140
RAD 140 is an exciting and exceptionally selective SARM that exerts potent anabolic effects yet only mild androgenic effects. It has been shown to promote lean muscle gains, promote neuroprotection and increase survival of adult-born neurons, function as a superior alternative to testosterone replacement therapy for a variety of potential indications, and selectively kill breast cancer cells.
*The information herein is for educational and informational purposes only. THIS PRODUCT IS FOR RESEARCH USE ONLY. For use in animal studies, all research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA).
Shipping Conditions: Ambient temperature.
Storage: Use within 12 months. Keep in a cool and dark location.
 C. P. Miller et al., “Design, synthesis, and preclinical characterization of the selective androgen receptor modulator (SARM) RAD140,” ACS Med. Chem. Lett., 2011.
 A. Jayaraman et al., “Selective androgen receptor modulator RAD140 is neuroprotective in cultured neurons and kainate-lesioned male rats,” Endocrinology, 2014.
 D. K. Hamson, S. R. Wainwright, J. R. Taylor, B. A. Jones, N. V. Watson, and L. A. M. Galea, “Androgens increase survival of adult-born neurons in the dentate gyrus by an androgen receptor-dependent mechanism in male rats,” Endocrinology, 2013.
 Z. Yu et al., “Selective androgen receptor modulator RAD140 inhibits the growth of androgen/estrogen receptor-positive breast cancer models with a distinct mechanism of action,” Clin. Cancer Res., vol. 23, no. 24, pp. 7608–7620, Dec. 2017.
 E. Hamilton et al., “Abstract OT1-02-02: A phase 1, first-in-human, multi-part study of RAD140, an oral nonsteroidal selective androgen receptor modulator, in postmenopausal women with hormone receptor positive breast cancer,” 2019, pp. OT1-02-02-OT1-02–02.
 J. P. Garay and B. H. Park, “Androgen receptor as a targeted therapy for breast cancer.,” Am. J. Cancer Res., 2012.
 S. Bhasin and R. Jasuja, “Selective androgen receptor modulators as function promoting therapies,” Current Opinion in Clinical Nutrition and Metabolic Care. 2009.
 C. Boni et al., “Therapeutic activity of testoterone in metastatic breast cancer,” Anticancer Res., 2014.
 K. A. Cadoo, A. Gucalp, and T. A. Traina, “Palbociclib: An evidence-based review of its potential in the treatment of breast cancer,” Breast Cancer: Targets and Therapy. 2014.
 E. Lim, M. Ni, S. Cao, A. Hazra, R. M. Tamimi, and M. Brown, “Importance of breast cancer subtype in the development of androgen-receptor-directed therapy,” Current Breast Cancer Reports. 2014.
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