[show abstract][hide abstract] ABSTRACT: Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR pathway-targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor that is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics, and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/d of ARN-509, whereas the same response required 100 mg/kg/d of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer.
Cancer Research 03/2012; 72(6):1494-503. · 8.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Specific retinoid X receptor (RXR) agonists, such as LG100268 (LG268), and the thiazolidinedione (TZD) PPARgamma agonists, such as rosiglitazone, produce insulin sensitization in rodent models of insulin resistance and type 2 diabetes. In sharp contrast to the TZDs that produce significant increases in body weight gain, RXR agonists reduce body weight gain and food consumption. Unfortunately, RXR agonists also suppress the thyroid hormone axis and generally produce hypertriglyceridemia. Heterodimer-selective RXR modulators have been identified that, in rodents, retain the metabolic benefits of RXR agonists with reduced side effects. These modulators bind specifically to RXR with high affinity and are RXR homodimer partial agonists. Although RXR agonists activate many heterodimer partners, these modulators selectively activate RXR:PPARalpha and RXR:PPARgamma, but not RXR:RARalpha, RXR:LXRalpha, RXR:LXRbeta, or RXR:FXRalpha. We report the in vivo characterization of one RXR modulator, LG101506 (LG1506). In Zucker fatty (fa/fa) rats, LG1506 is a potent insulin sensitizer that also enhances the insulin-sensitizing activities of rosiglitazone. Administration of LG1506 reduces both body weight gain and food consumption and blocks the TZD-induced weight gain when coadministered with rosiglitazone. LG1506 does not significantly suppress the thyroid hormone axis in rats, nor does it elevate triglycerides in Sprague Dawley rats. However, LG1506 produces a unique pattern of triglycerides elevation in Zucker rats. LG1506 elevates high-density lipoprotein cholesterol in humanized apolipoprotein A-1-transgenic mice. Therefore, selective RXR modulators are a promising approach for developing improved therapies for type 2 diabetes, although additional studies are needed to understand the strain-specific effects on triglycerides.
[show abstract][hide abstract] ABSTRACT: The farnesoid X receptor (FXR) is a nuclear receptor expressed in tissues exposed to high concentrations of bile acids such as the liver, kidney and intestine and functions as a bile acid sensor. FXR regulates the expression of various transport proteins and biosynthetic enzymes crucial to the physiological maintenance of lipids, cholesterol and bile acid homeostasis. The concept of reverse endocrinology, whereby the receptor is identified first, followed by the identification of ligands and the sequential elucidation of the physiological role of the receptor has been widely used for a number of orphan nuclear receptors. The design of synthetic high affinity ligands acting via these receptors not only helps to decipher the function of the receptor, but also should lead to the development of novel and highly specific drugs. The bile acid receptor FXR is a perfect example where this strategy helped with understanding the role of this receptor in cholesterol and bile acid homeostasis. Regulation of FXR through small-molecule drugs represents a promising therapy for diseases resulting from lipid, cholesterol and bile acid abnormalities.
Mini Reviews in Medicinal Chemistry 09/2005; 5(8):719-27. · 2.87 Impact Factor
[show abstract][hide abstract] ABSTRACT: Dermatological diseases such as acne, psoriasis, and various skin cancers affect approximately 24 million people in the US (17 million acne, 6.4 million psoriasis and 0.7 million skin cancer). In many cases, particularly for acne and psoriasis, these diseases have exhibited favourable responses to single agent or adjuvant retinoid therapy. When administered as both chemotherapeutic and chemopreventive agents, they offer a viable alternative to classical cancer chemotherapy. Although retinoid treatment has shown considerable promise, certain side-effects have limited their utility for chronic administration. Accordingly, there is considerable interest in developing novel retinoids that exhibit improvements in the side-effect profile, particularly for diseases that require chronic administration. Retinoids are potent biological modulators that exert their effects through intracellular receptors (retinoic acid receptors [RARs] and retinoid X receptors [RXRs]) where they regulate cellular proliferation, differentiation and programmed cell death. Currently, using a combination of molecular biology and synthetic chemistry, efforts are underway to fully characterise the biological role of individual retinoid receptor subtypes. Using receptor-selective retinoids, recent discoveries have assisted in clarifying the mechanism and biological function of retinoids and their receptors. It now appears that the RARs are implicated in the regulation of cellular proliferation and differentiation, whereas the RXRs function as modulators of programmed cell death or apoptosis. This suggests that diseases that are associated with abnormal proliferation and/or differentiation may be treatable with RAR active compounds. In fact, the data are supported by successful treatment of psoriasis, epithelial cancer and leukaemia with retinoids that preferentially activate the RARs. In contrast, retinoids that preferentially activate RXRs may be desirable for treatment of diseases for which enhancement of apoptosis is required. For example, they are potentially useful for treatment of cutaneous T-cell lymphoma and as chemopreventive agents . The mechanisms of action of these RXR mediated effects are under investigation. Finally, certain receptor subtypes are implicated in retinoid side-effects. For example, it has become increasingly evident that side-effects such as triglyceridaemia  and teratogenesis [3,4] can be correlated to activation of the RARs and not the RXR. These findings offer opportunities for developing a new generation of retinoids which exhibit improved therapeutic indices. Recently, novel treatment strategies have evolved including the application of receptor-selective synthetic retinoids, combination therapies with other hormones or chemotherapeutic agents, and novel formulations. This has resulted in a new generation of retinoids and retinoid treatments which are in clinical development and which exhibit improvements in the therapeutic index.
[show abstract][hide abstract] ABSTRACT: Complications of atherosclerotic cardiovascular disease due to elevated blood cholesterol levels are the major cause of death in the Western world. The liver X receptors, LXRalpha and LXRbeta (LXRs), are ligand-dependent transcription factors that act as cholesterol sensors and coordinately control transcription of genes involved in cholesterol and lipid homeostasis as well as macrophage inflammatory gene expression. LXRs regulate cholesterol balance through activation of ATP-binding cassette transporters that promote cholesterol transport and excretion from the liver, intestine, and macrophage. Although LXR agonists are known to delay progression of atherosclerosis in mouse models, their ability to abrogate preexisting cardiovascular disease by inducing regression and stabilization of established atherosclerotic lesions has not been addressed.
We demonstrate that LXR agonist treatment increases ATP-binding cassette transporter expression within preexisting atherosclerotic lesions, resulting in regression of these lesions as well as remodeling from vulnerable to stable lesions and a reduction in macrophage content. Further, using macrophage-selective LXR-deficient mice created by bone marrow transplantation, we provide the first evidence that macrophage LXR expression is necessary for the atheroprotective actions of an LXR agonist.
These data substantiate that drugs targeting macrophage LXR activity may offer therapeutic benefit in the treatment of atherosclerotic cardiovascular disease.
[show abstract][hide abstract] ABSTRACT: Peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha) is a transcriptional coactivator that is a key component in the regulation of energy production and utilization in metabolic tissues. Recent work has identified PGC-1alpha as a strong coactivator of the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha), implicating ERRalpha as a potential mediator of PGC-1alpha action. To understand the role of ERRalpha in PGC-1alpha signaling, a parallel approach of high-throughput screening and gene-expression analysis was used to identify ERRalpha small-molecule regulators and target genes. We report here the identification of a potent and selective ERRalpha inverse agonist that interferes effectively with PGC-1alpha/ERRalpha-dependent signaling. This inverse agonist inhibits the constitutive activity of ERRalpha in both biochemical and cell-based assays. Also, we demonstrate that monoamine oxidase B is an ERRalpha target gene whose expression is regulated by PGC-1alpha and ERRalpha and inhibited by the ERRalpha inverse agonist. The discovery of potent and selective ERRalpha modulators and their effect on PGC-1alpha signaling provides mechanistic insight into gene regulation by PGC-1alpha. These findings validate ERRalpha as a promising therapeutic target in the treatment of metabolic disorders, including diabetes and obesity.
Proceedings of the National Academy of Sciences 07/2004; 101(24):8912-7. · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: We show that the selective estrogen receptor modulator arzoxifene (Arz) and the rexinoid LG100268 (268) synergize to promote apoptosis in a rat model of estrogen receptor-positive breast carcinoma and in estrogen receptor-positive human breast cancer cells in culture. We also show that it is not necessary to administer Arz and 268 continuously during tumor progression to prevent cancer in the rat model because dosing of these drugs in combination for relatively short periods, each followed by drug-free rests, is highly effective. This new approach to chemoprevention uses high doses of drugs that are too toxic for long-term administration. However, when given for short periods, the agents are nontoxic and still induce apoptosis in breast cancer cells. We also show that the ability of the two drugs to induce apoptosis is the combined result of induction of transforming growth factor beta by Arz, together with inhibition of the prosurvival nuclear factor kappaB and phosphatidylinositol 3' kinase signaling pathways by 268. The new protocol we have developed for chemoprevention allows the efficacious and safe administration of 268 and Arz, and these agents now should be considered for clinical use.
Cancer Research 06/2004; 64(10):3566-71. · 8.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Members of the nuclear hormone receptor superfamily function as ligand-activated transcription factors to regulate genetic networks controlling cell growth and differentiation, inflammatory responses, and metabolism. The ability to modulate nuclear receptor-dependent gene expression with small molecules has made the superfamily a favored target for drug discovery. Not surprisingly, small molecules that regulate receptor activity are currently used to treat a number of human disorders. Over the last 10 years, the availability of a common platform of functional assays suitable for any nuclear receptor has facilitated the identification of endogenous and synthetic ligands that have been used as tools to uncover previously unanticipated endocrine signaling pathways. Recent progress in understanding the molecular basis for ligand-dependent gene regulation suggests that a new era of "designer" ligands with tissue- and/or gene-selective activity will quickly be upon us.
[show abstract][hide abstract] ABSTRACT: We explored the effects of bile acids on triglyceride (TG) homeostasis using a combination of molecular, cellular, and animal models. Cholic acid (CA) prevents hepatic TG accumulation, VLDL secretion, and elevated serum TG in mouse models of hypertriglyceridemia. At the molecular level, CA decreases hepatic expression of SREBP-1c and its lipogenic target genes. Through the use of mouse mutants for the short heterodimer partner (SHP) and liver X receptor (LXR) alpha and beta, we demonstrate the critical dependence of the reduction of SREBP-1c expression by either natural or synthetic farnesoid X receptor (FXR) agonists on both SHP and LXR alpha and LXR beta. These results suggest that strategies aimed at increasing FXR activity and the repressive effects of SHP should be explored to correct hypertriglyceridemia.
Journal of Clinical Investigation 06/2004; 113(10):1408-18. · 12.81 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recent studies have shown that genes involved in oxidative phosphorylation (OXPHOS) exhibit reduced expression in skeletal muscle of diabetic and prediabetic humans. Moreover, these changes may be mediated by the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). By combining PGC-1alpha-induced genome-wide transcriptional profiles with a computational strategy to detect cis-regulatory motifs, we identified estrogen-related receptor alpha (Erralpha) and GA repeat-binding protein alpha as key transcription factors regulating the OXPHOS pathway. Interestingly, the genes encoding these two transcription factors are themselves PGC-1alpha-inducible and contain variants of both motifs near their promoters. Cellular assays confirmed that Erralpha and GA-binding protein a partner with PGC-1alpha in muscle to form a double-positive-feedback loop that drives the expression of many OXPHOS genes. By using a synthetic inhibitor of Erralpha, we demonstrated its key role in PGC-1alpha-mediated effects on gene regulation and cellular respiration. These results illustrate the dissection of gene regulatory networks in a complex mammalian system, elucidate the mechanism of PGC-1alpha action in the OXPHOS pathway, and suggest that Erralpha agonists may ameliorate insulin-resistance in individuals with type 2 diabetes mellitus.
Proceedings of the National Academy of Sciences 05/2004; 101(17):6570-5. · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: The retinoid X receptor (RXR), a ubiquitously expressed intracellular receptor, regulates pathways controlling glucose, triglycerides, cholesterol, and bile acid metabolism. In addition to its role in those metabolic pathways, we reported that RXR activation with a pan agonist [e.g. LG100268 (LG268)] decreases both body weight gain (BWG) and food consumption (FC) in obese, insulin-resistant rodents. In parallel with those changes in energy balance, we show here that activation of RXR pathways results in adipose tissue remodeling, particularly within sc fat where the rate of apoptosis is increased 5-fold. This change may underlie the selective decrease in fat mass observed in Zucker fatty rats treated with LG268 for 6 wk. Because FC is strongly correlated with BWG in treated animals, we hypothesized that regulation of FC might be the primary mechanism underlying reduced BWG during RXR agonist administration. Importantly, decreased FC is due to decreased meal size, suggestive of induced satiety rather than malaise and/or aversion to food. Furthermore, administration of LG268 directly into the brain via intracerebroventricular injection also reduces FC, BWG, and insulin, whereas the elevation in triglycerides observed after oral administration is absent. The latter observation suggests that RXR actions on energy balance and lipid homeostasis are separable. Therefore, ligand-mediated activation of either an RXR homodimer or an unidentified heterodimeric complex regulates pathways controlling energy balance at least in part via a central nervous system-mediated mechanism.
[show abstract][hide abstract] ABSTRACT: Members of the nuclear hormone receptor superfamily function as ligand-activated transcription factors to regulate genetic networks controlling cell growth and differentiation, inflammatory responses, and metabolism. The ability to modulate nuclear receptor-dependent gene expression with small molecules has made the superfamily a favored target for drug discovery. Not surprisingly, small molecules that regulate receptor activity are currently used to treat a number of human disorders. Over the last 10 years, the availability of a common platform of functional assays suitable for any nuclear receptor has facilitated the identification of endogenous and synthetic ligands that have been used as tools to uncover previously unanticipated endocrine signaling pathways. Recent progress in understanding the molecular basis for ligand-dependent gene regulation suggests that a new era of “designer” ligands with tissue- and/or gene-selective activity will quickly be upon us.
[show abstract][hide abstract] ABSTRACT: The retinoid X receptor (RXR) is essential as a common heterodimerization partner of several nuclear receptors (NRs). However, its function as a bona fide receptor for endogenous ligands has remained poorly understood. Such a role would depend on the existence of RXR activating ligands in vivo and on the ability of such ligands to influence relevant biological functions. Here we demonstrate the presence of endogenous RXR ligands in the embryonic central nervous system (CNS) and show that they can activate heterodimers formed between RXR and the orphan NR Nurr1 in vivo. Moreover, RXR ligands increase the number of surviving dopaminergic cells and other neurons in a process mediated by Nurr1-RXR heterodimers. These results provide evidence for a role of Nurr1 as a ligand-independent partner of RXR in its function as a bona fide ligand-activated NR. Finally, our findings identify RXR-Nurr1 heterodimers as a potential target in the treatment of neurodegenerative disease.
Genes & Development 01/2004; 17(24):3036-47. · 12.44 Impact Factor
[show abstract][hide abstract] ABSTRACT: Liver X receptors (LXRs) regulate the expression of genes involved in cholesterol and fatty acid homeostasis, including the genes for ATP-binding cassette transporter A1 (ABCA1) and sterol response element binding protein 1 (SREBP1). Loss of LXR leads to derepression of the ABCA1 gene in macrophages and the intestine, while the SREBP1c gene remains transcriptionally silent. Here we report that high-density-lipoprotein (HDL) cholesterol levels are increased in LXR-deficient mice, suggesting that derepression of ABCA1 and possibly other LXR target genes in selected tissues is sufficient to result in enhanced HDL biogenesis at the whole-body level. We provide several independent lines of evidence indicating that the repressive actions of LXRs are dependent on interactions with the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptors (SMRT). While dissociation of NCoR and SMRT results in derepression of the ABCA1 gene in macrophages, it is not sufficient for derepression of the SREBP1c gene. These findings reveal differential requirements for corepressors in the regulation of genes involved in cholesterol and fatty acid homeostasis and raise the possibility that these interactions may be exploited to develop synthetic ligands that selectively modulate LXR actions in vivo.
Molecular and Cellular Biology 09/2003; 23(16):5780-9. · 5.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: The purine anti-metabolite 6-mercaptopurine is one of the most widely used drugs for the treatment of acute childhood leukemia and chronic myelocytic leukemia. Developed in the 1950s, the drug is also being used as a treatment for inflammatory diseases such as Crohn's disease. The antiproliferative mechanism of action of this drug and other purine anti-metabolites has been demonstrated to be through inhibition of de novo purine synthesis and incorporation into nucleic acids. Despite the extensive clinical use and study of 6-mercaptopurine and other purine analogues, the cellular effects of these compounds remain relatively unknown. More recently, purine anti-metabolites have been shown to function as protein kinase inhibitors and to regulate gene expression. In an attempt to find small molecule regulators of the orphan nuclear receptor Nurr1, interestingly, we identified 6-mercaptopurine as a specific activator of this receptor. A detailed analysis of 6-mercaptopurine regulation of Nurr1 demonstrates that 6-mercaptopurine regulates Nurr1 through a region in the amino terminus. This activity can be inhibited by components of the purine biosynthesis pathway. These findings indicate that Nurr1 may play a role in mediating some of the antiproliferative effects of 6-mercaptopurine and potentially implicate Nurr1 as a molecular target for treatment of leukemias.
Journal of Biological Chemistry 08/2003; 278(27):24791-9. · 4.65 Impact Factor