PREFACE [Hot topic: Nuclear Hormone Receptor Modulators as Targets for Drug Discovery (Guest Editor: Timothy Grese)]

Over the last several years, the nuclear hormone receptor superfamily has enjoyed a renaissance as a target of pharmaceutical research. These ligand-gated transcription factors regulate a plethora of biological activities and exert key roles in the pathophysiology of major disease states including diabetes, obesity, osteoporosis, inflammation, atherosclerosis, and congestive heart failure, just to name a few. The utilization of nuclear hormone receptor ligands as pharmacological agents dates at least to the early part of the 20th century, when the hormonal components of glandular extracts were first isolated and characterized. During the 1950s and 60s, pharmaceutical investment in the steroids was at its heyday, leading to the development of contraceptives, anti-inflammatory drugs, anabolic agents, and hormone replacement therapies. Gradually the emphasis began to shift toward steroid receptor antagonists and nonsteroidal ligands, particularly in the area of cancer research. With the development of molecular biology in the 1980s and 90s, techniques for the cloning, expression, purification, and sequencing of the receptor proteins began to appear. These tools allowed a more critical dissection of the elements of biological activity, and for the first time, the signaling mechanisms of nuclear hormone receptors began to be elucidated. The possibility that particular ligands might discriminate between the positive and negative effects of the steroids was advanced, culminating with the development of the first Selective Estrogen Receptor Modulators (SERMs). At the same time, new members of the nuclear hormone receptor superfamily were being identified, spawning significant research investment in anticipation that they might also serve as pharmacological targets. Indeed the PPAR's, early members of this “orphan” receptor group, were found to be the molecular target for the fibrates and the thiazolidinediones. The complete sequencing of the human genome has now defined the total number of members of the nuclear receptor family at 48. At the time of this writing, natural or synthetic ligands have been described for approximately 30 of these proteins. The application of modern methods of compound screening and structural biological techniques has greatly augmented our ability to identify ligands for the orphan receptors, and enabled the determination of their innate pharmacology. The reviews in this edition highlight some of the most important areas of current pharmaceutical research on nuclear hormone receptors. In each case, whether classical steroid receptors, orphan receptors, or structural biology, the clear message is that we are still very early in our understanding of these drug targets. The opportunities for pharmaceutical development continue to grow and will provide a fertile area for scientific research throughout the foreseeable future.