Selective Glucocorticoid Receptor Agonists and Modulators (SEGRAMs)

Dear Colleagues,

Glucocorticoids (GCs) are steroid hormones that regulate a variety of physiological processes including development, metabolism, homeostasis, immune response, and apoptosis in a cell-specific manner. The biological actions of GCs are mediated through the ubiquitously expressed glucocorticoid receptor (GR), a ligand inducible transcription factor that is activated upon GC binding. Activated GR regulates the transcription of several hundreds of target genes either through direct binding to DNA elements known as glucocorticoid responsive elements (GREs, ‘classical model’ associated mainky with transactivation), or through interaction with other transcription factors such as Nuclear factor-kappa B (NF-κB, ‘non-classical model’ associated mainly with transrepression).

GCs are potent anti-inflammatory drugs that have been used to treat inflammatory and autoimmune diseases since the late 1940s. However, the clinical use of GCs is often accompanied by a wide range of adverse side effects, such as metabolic disorders including type-2 diabetes, fat redistribution, osteoporosis, skin and muscle atrophy, hypothalamo-pituitary-adrenal (HPA) axis insufficiency and mood disorders. Due to the increasing therapeutic application of GCs, there is an unmet need for novel drugs with the therapeutic advantages of classical GCs but with a reduced side effect profile. It is widely accepted that most side effects of GCs are mediated by transactivation, whereas the anti-inflammatory effects are mainly due to transrepression, including the inhibition of NF-κB. Therefore, identifying novel GR ligands that selectively favor the anti-inflammatory action of GCs over undesirable side effects (Selective Glucocorticoid Receptor Agonists and Modulators, SEGRAMs) could enhance the clinical performance of GCs.

A large number of putative SEGRAMs, some developed by big Pharma teams, has been designed.  While the development of a fully selective compound is of great interest, the complexity of the gene, cell and tissue specificity of GC signaling questions our ability to completely uncouple the therapeutic and side effects of SEGRAMs. Furthermore, other discoveries suggest that the transactivation of anti-inflammatory acting genes is involved in the anti-inflammatory action of GCs. The ‘transactivation vs. transrepression’ concept is probably too simplistic and the molecular mechanisms underlying the putative selective action of SEGRAMs remain largely unknown and warrant further research.

This Special Issue aims to elucidate the development of novel SEGRAMs and to explore the molecular and cellular mechanisms underlying their selective function. We welcome the submission of original research articles and reviews.

Dr. Dimitra Mitsiou
Guest Editor

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