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    • br Experimental br Acknowledgments This project was generous

    2021-12-03


    Experimental
    Acknowledgments This project was generously supported by Grünenthal GmbH and IECB. We also thank the staff members of the technical platform of IECB and Grünenthal GmbH for their availability and their skills.
    Introduction Glucocorticoids (GCs) are essential steroid hormones that are secreted by the adrenal cortex. GCs regulate a variety of physiological processes including development, metabolism, homeostasis and apoptosis in a cell-specific manner. The biological actions of GCs are mediated through the ubiquitously expressed glucocorticoid receptor (GR; NR3C1), a ligand inducible transcription factor that belongs to the nuclear receptor superfamily. GC binding to GR regulates transcription of several hundreds of target genes either through direct binding of activated GR to DNA elements known as glucocorticoid responsive elements (GREs; ‘classical model’ mainly associated with transactivation) or through interaction with other transcription factors including Nuclear factor-kappa B (NF-kB; ‘non-classical model’ associated with transrepression) [[1], [2], [3], [4]]. NF-kB is a family of constitutively expressed transcription factors critically involved in many biological processes such as cell proliferation, development, and inflammatory and immune responses. Inactive NF-kB exists as a dimer (composed mainly of p50 and p65) that remains in the cytosol due to its association with the inhibitory protein I-kBα (NF-kB Inhibitor alpha). In response to diverse inflammatory stimuli, I-kBα is phosphorylated and rapidly degraded thus releasing the NF-kB dimer (activated NF-kB) which translocates to the nucleus, binds to NF-kB response elements (NF-kB RE) and regulates gene expression. NF-kB target genes encode various proteins such as pro-inflammatory cytokines, chemokines, receptors and adhesion molecules [5]. The crosstalk between GR and NF-kB signalling has been the major focus of research for many years and the most extensively studied case has been the transrepression of NF-kB by GR initially in model NF-kB RE-dependent promoters. Using global analysis of GR-NF-kB crosstalk we have recently shown that co-activation of GR and NF-kB leads to their mutual recruitment on novel chromatin Protein A/G and alters the repertoire of genes regulated by each factor separately [6]. GCs are potent anti-inflammatory drugs that have been used since the late 1940s for the treatment of inflammatory and autoimmune diseases. However, GC therapy is often accompanied by a wide range of adverse side effects, such as metabolic disorders including type-2 diabetes (resulting from hyperglycemia and a decreased carbohydrate tolerance), fat redistribution, osteoporosis, skin and muscle atrophy, hypothalamo-pituitary-adrenal (HPA) axis insufficiency and mood disorders [7]. Nevertheless, the therapeutic usage of GCs is continuously rising, as well as the total market size. At the moment, there is an unmet high need for new drugs with the therapeutic advantages of classical GCs, but with a reduced profile of side effects. It is widely accepted that the majority of side effects of GCs are mediated by transactivation whereas the anti-inflammatory effects are mainly due to transrepression, including primarily inhibition of NF-kB action. Therefore, uncoupling anti-inflammatory effects from side effects by identifying novel GR ligands that preferentially mediate transrepression rather than transactivation (Selective Glucocorticoid Receptor Agonists, SEGRA) could improve the clinical performance of long-term treatments with GCs, where adverse side effects should be taken into consideration. GR has the capacity to bind a wide range of ligands a property that has been exploited for the design of SEGRA. The development of new SEGRA is based on the ability of GR to bind both steroidal as well as non-steroidal ligands of impressively different size and structure as compared to dexamethasone (Dex, a synthetic GC). Crystal structure analysis revealed that deacylcortivazol (DAC, a phenylpyrazolo glucocorticoid) doubled the ligand binding domain (LBD) of GR [8]. Notably, a series of non-steroidal GR agonists bearing an aminopyrazole moiety with excellent selectivity for GR over other steroid hormone receptors, were also found to be well accommodated in the extended GR binding site [9]. A rather large number of putative SEGRA, some developed by big pharma teams (e.g. GlaxoSmithKline, Abbott, Bayer Schering Pharma, Bristol-Myers Squibb, Merck, Boehringer Ingelheim Pharmaceuticals) have been reported [[9], [10], [11], [12], [13]]. Although none of these compounds has reached the clinic yet, these studies substantially contributed to the current knowledge on SEGRA action but also pointed to certain limitations. Furthermore, other discoveries suggest that GR-dependent transactivation of anti-inflammatory genes is likely to be an important part of the mechanism of anti-inflammatory action of GCs [14,15]. The ‘transactivation vs transrepression’ concept is probably too simplistic and the molecular mechanisms underlying the putative selective action of SEGRA remains largely unknown and warrants further research.