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Editorial [Hot Topic: Nuclear Receptors as Targets in Drug Discovery: Medicinal Chemistry and Therapeutic Potential (Guest Editor: Mary J. Meegan)]

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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.
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Document Type: Research Article

Affiliations: School of Pharmacy and Pharmaceutical Sciences Trinity College Dublin, Ireland.

Publication date: February 1, 2006

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