Current Topics in Medicinal Chemistry - Volume 6, Issue 3, 2006

Nuclear receptors have become an important focus of clinical and pharmaceutical investigation as they represent targets for many of the key lipophilic hormones such as steroids, thyroxine and retinoic acid. These receptors include the Androgen Receptor (AR), Estrogen Receptor (ER), Progesterone Receptor (PR), Glucocorticoid receptor (GR), Peroxisome Proliferator-Activated Receptor (PPAR), Thyroid Receptor (TR), Vitamin D Receptor and the various Steroid Receptor associated proteins (SRAPR). These receptors function as ligand dependent transcriptional regulators and are involved in the regulation of many critical biochemical processes such as cell differentiation, development and proliferation. The understanding of the complex chemical structure and biochemical function of the nuclear receptor family has expanded considerably in recent years in the areas of hormonal signal transduction pathways and elucidation of the molecular mechanisms by which gene activity is directly regulated by the hormone receptor complex. The review topics highlight the central role of the estrogen receptor (ER) as a target in breast cancer including the development of acquired resistance to exhaustive use of endocrine therapy and the mechanism of endocrine based therapy resistance. The Estrogen-related Receptors (ERR) are now recognized as potential therapeutic targets and clinical markers in breast cancer. Identification of the Estrogen Receptor (ER) as a key mediator of the proliferation of breast cancer together with recognition of its involvement in pathways leading to osteoporosis and coronary heart disease, has resulted in the discovery and design of compounds with the ability to modulate its actions (SERMs). The recent phenomenal growth in potential new molecular targets, together with automation, miniaturisation and combinatorial chemistry have resulted in a huge increase in the number of compounds available for conventional high throughput screening (HTS). The possibilities for modulation of biochemical pathways involving the ER are diverse and application of computational techniques to a number of new targets may assist in the discovery of compounds that could activate subsets of the ER pathway. Modulation of the androgen receptor (AR) has the potential to be an effective treatment for hypogonadism, andropause, and associated conditions such as sarcopenia, osteoporosis, benign prostatic hyperplasia, and sexual dysfunction. Side effects associated with classical anabolic steroid treatments have driven the quest for drugs that demonstrate improved therapeutic profiles. Novel, non-steroidal compounds that show tissue selective activity and improved pharmacokinetic properties have been developed. An overview of current advances in the development of selective androgen receptor modulators (SARMs) provides an indication of the therapeutic potential of these ligands. Determination of the appropriate clinical dose of a steroid drug to be both therapeutically effective and to avoid the undersirable side effects is a complex problem due to interacting factors and systems. However, approaches towards the prediction of EC50 values for steroid induction of specific genes should lead to specificy in clinical treatment. The nuclear receptor family are clearly recognized as major therapeutic targets for the development of new pharmaceutical agents that can be useful for the treatment of hormone dependent neoplasias and related diseased states.

The estrogen receptor α (ERα) has proven to be the single most important target in breast cancer over the last 30 years. The use of the selective ER modulator (SERM) tamoxifen for the treatment and prevention of breast cancer has changed therapeutics. The SERM raloxifene, approved for the treatment of osteoporosis, lacks tamoxifen's increased risk for endometrial cancer and is being evaluated for the prevention of breast cancer. Other SERMs approved or under development for use against breast cancer or osteoporosis include toremifene, GW5638, GW7604 (the active metabolite of GW5638), idoxifene, lasofoxifene, arzoxifene, bazedoxifene, EM-800 and acolbifene (the active metabolite of EM- 800). Aromatase inhibitors (AIs) have recently proven to be more efficacious than tamoxifen as first-line therapy, efficacious for second-line therapy (e.g. against tamoxifen-resistant disease), and useful for extended adjuvant therapy after tamoxifen. The AIs include the non-steroidal agents letrozole and anastrole, and the steroidal agent exemestane. The pure antiestrogen fulvestrant has proven to be just as effective as AIs. Other pure antiestrogens, ZK-703, ZK-253, RU 58668 and TAS-108 show great promise. The development of resistance to endocrine therapy remains a clinically important problem, and laboratory models based on human breast cancer cells grown as tumors in immune-compromised mice have led to important insights into this problem. Progesterone receptor-negative status of ER-positive breast cancers may reflect altered growth factor receptor signaling, and helps to explain why this subclass of tumors exhibits lower response rates to tamoxifen compared to cancers typed progesterone receptor-positive. Crosstalk among plasma membrane-localized ER, growth factor receptor signaling, and nuclear-localized ER provide further insights into antihormonal-resistant breast cancer.

While estrogen receptor (ER)-targeted therapeutics have clearly been a success in the treatment of breast cancer, the orphan estrogen-related receptors (ERRs) represent novel targets for future development. The ERRs, comprising ERRα, ERRβb and ERRγ, bind and regulate transcription via estrogen response elements (EREs) and extended ERE half-sites termed ERR response elements (ERREs), but do not bind endogenous estrogens. The emerging role of ERRα and ERRγ in modulating estrogen responsiveness, substituting for ER activities, and serving as prognosticators in breast and other cancers is providing an impetus for the identification of compounds which target these proteins. Moreover, ERRα plays a role in energy homeostasis and will likely be targeted for the treatment of metabolic disorders. Multiple classes of synthetic ligands have already been identified. The phytoestrogens genistein, daidzein, biochanin A and 6,3'4'-tryhydroxyflavone have been reported as ERRa agonists. The phenolic acyl hydrazones GSK4716 and GSK9089 act as selective agonists of ERRβ and ERRγ. The organochlorine pesticides toxaphene and chlordane, and the synthetic compound XCT790 antagonize ERRα. The synthetic estrogen diethylstilbestrol antagonizes all three ERRs. The selective estrogen receptor modulators 4-hydroxytamoxifen and 4-hydroxytoremifene antagonize ERRγ. The rational development of synthetic ligands for the ERRs may soon provide new agents to supplement the repertoire of antihormonal therapies to combat breast cancer. Moreover, expression of ERRs in other cancers and metabolic disorders may provide a targeted treatment strategy for these patients as well.

Identification of the Estrogen Receptor (ER) as a key mediator of the proliferation of breast cancer, and its involvement in pathways leading to osteoporosis and coronary heart disease, has resulted in a surge to discover and design compounds with the ability to modulate its actions (SERMs). Concurrently, a dramatic increase in the number of crystal structures of the ER has led to a more in depth understanding of the governing mechanisms involved in ER modulation. Entwining computational techniques with the availability of 3D structural data, has allowed not only the rational design of potent inhibitors of the ER, but also its incorporation in Virtual Screening (VS) in the search for novel chemotypes that can modulate the ER. An important initial step in the VS process is to filter towards molecules that occupy similar chemical space to a set of known actives prior to docking. We illustrate through Principal Component Analysis (PCA) of 145 descriptors the region of chemical space antiestrogens occupy compared with 'drug-like' space. We also review all available studies involving validation of several docking algorithms utilizing the ER, ultimately focusing on analysis of Enrichment (E) rates and False Positive (FP) rates to illustrate the successes attributed to each docking algorithm. Finally, we relate the recent discovery of non-genomic mechanisms of the ER and subsequently present a model involving a recently identified alternative, second binding-pocket of the ER in our laboratory through cavity analysis that suggests how the same receptor can invoke these, 'classical' and rapid responses concurrently.

Modulation of the androgen receptor has the potential to be an effective treatment for hypogonadism, andropause, and associated conditions such as sarcopenia, osteoporosis, benign prostatic hyperplasia, and sexual dysfunction. Side effects associated with classical anabolic steroid treatments have driven the quest for drugs that demonstrate improved therapeutic profiles. Novel, non-steroidal compounds that show tissue selective activity and improved pharmacokinetic properties have been developed. This review provides an overview of current advances in the development of selective androgen receptor modulators (SARMs).

The position of the dose-response curve for steroid-regulated gene expression determines how much variation in response will accompany the normal physiological changes in circulating steroid. Over the last several years, it has become clear that the concentration of steroid hormone required for half-maximal induction or repression by a given receptor-steroid complex, which is normally called the EC50, is not constant for all responsive genes. Thus, the position of the dose-response curve can change so that a single concentration of steroid produces very different percentages of maximal activity. This, in turn, allows for the differential expression of genes by a common steroid hormone concentration during development, differentiation, and homeostasis. Here we review the variety of factors that influence the EC50 and position of the dose-response curve for steroid hormone receptors, discuss what is known about the mechanisms, and highlight promising areas for future research.