Editorial [Hot Topic: Nuclear Receptors as Drug Discovery Targets (Executive Editor: Sunil Nagpal)]

Nuclear receptor (NR) proteins are ligand-dependent transcription factors that belong to the superfamily of steroid/thyroid/retinoid/vitamin D receptors. NR family members play important roles in cell growth, differentiation, homeostasis, metabolism and development. NRs are modular proteins that contain three distinct functional domains. An Nterminal domain containing a ligand-independent activation function, AF-1, a middle zinc-finger containing DNA binding domain (DBD) and C-terminal ligand binding domain (LBD) that also harbors a ligand-dependent transactivation function, AF-2. The activity of NR proteins is modulated by ligand binding to their LBDs that results in a conformational change leading to either transactivation or transrepression of target gene expression in a cell/tissue and promoter/gene-context dependent manner. NRs are one of the best therapeutic targets since their activities could be modulated by small molecules, leading to subtle changes in gene expression in the desired direction and normalization of the altered physiological/pathological phenotype. In the past decade, a number of molecular, genetic, structural and pharmacological studies have contributed to increased understanding of the molecular pathways involved in NR action. These studies have identified not only novel mechanisms of NR action but also provided new disease targets for small molecule ligands. These studies in addition have yielded novel molecular assays for the rapid identification of compounds with the desired pharmacological profile and have helped set a stage for the rational design of the next generation of pharmaceuticals. There are 48 members of the NR superfamily in the human genome. Interestingly, all the NRs (except LXR), whose ligands are known, are successful therapeutic targets. Therefore, synthetic and/or natural ligands of steroid hormone receptors (AR, MR, PR and GR), RAR, RXR, VDR, TR and PPAR, are currently marketed drugs (Table I). Further, the involvement of even orphan NRs whose ligands have not been identified, and LXRs, in important physiological or metabolic processes provides the rest of NRs with a high level of validation as potential therapeutic targets. NR based drugs account for approximately 10-15% of the total worldwide pharmaceutical market. Most of these drugs are best currently available options for the treatment of conditions associated with significant morbidity and mortality. A number of these treatments are currently in vogue even though their use is accompanied by unwanted side effects. For example, although glucocorticoids (GR agonists), one of the most successful classes of pharmaceuticals, are widely used for the treatment of inflammatory diseases (rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, etc.), their use is associated with osteoporosis, hyperglycemia, hypertension, sleep disturbances and psychosis. Similarly, topical corticosteroids cause skin thinning and tachyphylaxis and thus cannot be applied for generally more than two weeks. Therefore, there is an urgent need for the development of safer oral and topical glucocorticoids without the above-mentioned side effects. PPARγ ligands, Actos and Avandia, are medicines of choice for the treatment of type II diabetes but their use is accompanied by unwanted side effects of weight gain and edema. Further, widespread use and development of VDR ligands for osteoporosis and inflammatory indications is hampered by their undesired side effect of hypercalcemia/hypercalciuria. Increased biology of NR action has resulted in the elucidation of the mechanisms underlying therapeutic actions and side effects. Recently, considerable pharmaceutical research has been directed towards identifying efficacious NR ligands devoid of their classical side effects. While it is not possible to cover all the NRs in a single issue, here a number of leading drug hunters provide a glimpse in the drug discovery efforts on selected members of this superfamily (MR, PR, Retinoid Receptors, FXR, VDR, PPARs and LXRs). In this decade, we hope to see the emergence of novel drugs from some of these efforts.