“The Solvay Pharmaceuticals Conferences: where industry meets academia in a search for novel therapies”

Nuclear Receptors Take Off

The cloning of the first nuclear receptor cDNA encoding the human glucocorticoid receptor was described in 1985 by the team of Evans [1]. Over the next 25 years a dramatic growth of knowledge on nuclear receptors followed this discovery [2]. The knowledge on nuclear receptors has delivered novel therapies for lipid control and hormone replacement, and for management of cancers and diabetes, and millions of humans were subjected to therapies with nuclear receptor modulators over last decades [2,3].

Nuclear receptors are a family of transcription factors consisting of 49 members identified in the human genome [3]. Nuclear receptors regulate transcription by binding to response elements in the regulatory regions of target genes and thereby affect expression of genes involved in differentiation, growth, lipid homeostasis, inflammation and immunity. Therefore, nuclear receptors are attractive molecular targets for design of therapy for diabetes, obesity, atherosclerosis, cancer, inflammation and neurodegeneration.

Many drugs from the armamentarium of contemporary physicians are acting on nuclear receptors: estrogens for hormone replacement therapy, anti-estrogens for treatment of cancer, steroids for treatment of inflammatory disorders, fibrates for treatment of dyslipidemia, and thiazolidinediones for therapy of diabetes [2].

Through their distinct tissue distribution and specific target gene activation, the peroxisome proliferator-activated receptors (PPARs) α, γ and δ modulate diverse aspects of fatty acid metabolism, energy balance, insulin sensitivity, glucose homeostasis and inflammatory responses. Two types of PPARs are marketed: PPARα is the target for fibrates (hypolipidemic drugs), PPARγ is the target for thiazolidinediones (anti-diabetic drugs).

The Liver X Receptors (LXRs) modulate macrophage cholesterol efflux and repress the expression of pro-inflammatory genes. Therefore, LXRs are considered as a target for the treatment of atherosclerosis (prevention and reversal). LXRs are key players in inflammatory conditions such as rheumatoid arthritis, inflammatory bowel diseases and diabetes. Through action on both cholesterol homeostasis and inflammatory processes, LXRs are considered as prospective targets for design of novel therapies for Alzheimer's disease.

Thyroid hormone signals are transduced by two distinct nuclear receptors: TRα and TRβ. TRα mediates the effects of thyroid hormones on heart rate whereas TRβ mediates cholesterol lowering effects. Therapeutic use of these receptors has not substantiated yet, but both are carefully considered by drug developers.

In addition to transcriptional regulation of metabolic pathways, nuclear receptors regulate the expression of genes participating in inflammatory cascades as well as genes promoting cellular growth and differentiation. Therefore, nuclear receptors continue to be important for the development of novel therapies of inflammation, cancer and neurodegeneration.

This volume contains papers from the Eight Solvay Pharmaceuticals Conference on Nuclear Receptors as Molecular Targets for Cardiometabolic and Central Nervous System Diseases held in Nice (France) April 11–13, 2007.

It has been the aim of these conferences to bring together scientists from academia and from industry in order to stimulate dialog between them in a congenial setting. The focus of this conference centered on the mechanistic involvement of nuclear receptors in cardiological, metabolic and neurological disorders, on possible explanation of pathways involved in pathogenesis, on susceptibility to and prevention of metabolic and neurological disorders and on the aspects of drug finding including chemistry and rational drug design. New technologies were highlighted including gene expression, novel approaches towards epigenetics, physiological monitoring and prospective use of novel therapeutics.

W. Cautreels, C. Steinborn, L. Turski

References

[1] S.M. Hollenberg, C. Weinberger C, E.S. Ong et al. Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature 318 (1985) 635–641.

[2] R.M. Evans. The nuclear receptor superfamily: a rosetta stone for physiology. Mol. Endocrinol. 19 (2005) 1429–1438.

[3] D.L. Morganstein and M.G. Parker. Role of nuclear receptor coregulators in metabolism. Exp. Rev. Endocrinol. Metab. 2 (2007) 797–807.