Editorial [Hot Topic: The Medicinal Chemistry of Agents Targeting the Nuclear Hormone Receptor Guest Editor: John Regan ]

The human nuclear hormone receptor (NHR) family consists of 48 transcription regulators which, in turn, control a vast assortment of biological functions. Receptor activation occurs upon binding with a variety of both high- and low-affinity ligands including steroids, prostanoids, retinoids, Vitamin D, oxysterols and bile acids. Many of these receptors serve as the basis for clinical intervention and involve treatments for breast and prostate cancers, coronary heart disease, diabetes and osteoporosis. However, 40% of the receptors are classified as “orphan receptors” since their physiological functions and binding ligands are unknown. Due to the established ability to identify treatments for diseases associated with NHRs, targeting these receptors for drug discovery endeavors after they become deorphanized will likely become a reality. For now, the immensely complicated processes involving the interplay of NHRs, ligands, cofactors and repressors affecting gene regulation, either through repression or up-regulation, are challenging variables to control in laboratory settings. Adding to these issues is the fact that, in many cases, confirmation of the validity of cellular and animal models must wait as results from clinical trials unfold. This thematic issue of Current Topics in Medicinal Chemistry entitled “The Medicinal Chemistry of Agents Targeting the Nuclear Hormone Receptor” encompasses reviews of the most recent advances and solutions to many of the problems associated with developing drugs whose targets are the NHRs. These six articles focus on steroid or endocrine hormone receptors - glucocorticoid (agonists and antagonist), estrogen, progesterone - and the metabolic receptors PPAR and LXR. The reader will readily appreciate the high quality of scientific investigations that reveal some of nature's most tightly held secrets. Despite the complex webs of chemical and biological interactions, significant drug discovery advances are being achieved. I would like to acknowledge the authors for their substantial contributions to the field of NHR research and thank them for writing these comprehensive and informative reviews. Hopefully these articles will inspire others to continue investigating innovative approaches to NHR-based therapies that will be capable of intervening in serious and often life-threatening diseases.