Nuclear receptors drive many critical processes ranging from metabolism to reproduction by serving as ligand-activated transcription factors. They also represent a lucrative area for drug discovery as evidenced by current therapies utilizing glucocorticoids for asthma, estrogens for hormone-replacement therapy, and retinoids for acne.
Current efforts continue to take aim at developing compounds that improve function and target specificity while reducing untoward effects.
Last month’s “Endo 2011” meeting described emerging concepts and new studies that are helping to unravel the complex interactions of nuclear receptors and their ligands. Topics included a perspective on the state of the field, new research delineating pathways, and improved strategies for developing novel therapeutic ligands.
“Manipulation of nuclear receptors has much potential to cure diseases,” says John D. Baxter, M.D., chief of the division of endocrinology and director of the Genome Medicine Program at Methodist Hospital Research Institute. Dr. Baxter presented a perspective on the past, the present, and the future of the field.
“This has been a robust field that has probably not received the attention it deserves for its potential or for its past discoveries. At least 20 percent of all prescriptions are for drugs that bind nuclear receptors.”
Assessing the field at the present moment, Dr. Baxter reported, “We are able to manipulate nuclear receptors for a growing list of diseases. We have estrogens and androgens such as testosterone, and antagonists to these receptors.
“We use retinoids to treat skin diseases, glucocorticoids such as prednisone to treat inflammatory states, and mineralocorticoid antagonists to treat heart failure. I work with the thyroid receptor that impacts lipid disorders, obesity, diabetes, fatty liver, and atherosclerosis.”
In the past, Dr. Baxter summarized that “key discoveries were initially made in the late 1950s and early 1960s. These included demonstrating that steroid hormones could be selectively taken up in hormone-responsive tissues, an emerging recognition of the presence of receptors, and the landmark finding that these receptors served as transcription factors.
“We also learned that there are variations in receptor numbers and in their ability to act that led to the huge field of hormone resistance, important for many diseases.
“Later,” he continued, “the mosaic nature of the receptor was identified in that these are single polypeptide chain proteins with domains that serve multiple functions including promotion of binding to DNA and interactions with coregulators that connect receptors to downstream receptor actions.
“Such binding transmits information to promote regulation of transcription and cloning of coregulators, important in many diseases. This greatly enhanced our understanding of receptor function.
“Cloning of receptor genes led to realization that there are many more receptors than we thought existed and to the discovery of many additional receptors that have important roles in disease. Determinations of receptor structures at atomic resolution greatly enhanced our ability to design drugs that target receptors and to understand receptor mechanisms of action.”
For the future, Dr. Baxter sees a growing increase in using these new discoveries to better understand and treat pathologies.
“Structural modeling provides an enormous help to understand the structure/function of receptors to assist with improved drug design. This continues to be a massively important field for drug discovery. As we better determine where and how drugs act, we can develop improved drugs using combinatorial chemistry to more selectively target specific nuclear receptors.”
As a final note, Dr. Baxter said he hopes that Nobel prizes are on the horizon for the investigators that have made important discoveries in this field and the widespread impact that has resulted from them.