Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds

Abstract

Glucocorticoids remain the frontline treatment for inflammatory disorders, yet represent a double-edged sword with beneficial therapeutic actions alongside adverse effects, mainly in metabolic regulation. Considerable efforts were made to improve this balance by attempting to amplify therapeutic beneficial anti-inflammatory actions and to minimize adverse metabolic actions. Most attention has focused on the development of novel compounds favoring the transrepressing actions of the glucocorticoid receptor, assumed to be important for anti-inflammatory actions, over the transactivating actions, assumed to underpin the undesirable actions. These compounds are classified as selective glucocorticoid receptor agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). The latter class is able to modulate the activity of a GR agonist and/or may not classically bind the glucocorticoid receptor ligand-binding pocket. SEGRAs and SEGRMs are collectively denominated SEGRAMs (selective glucocorticoid receptor agonists and modulators). Although this transrepression vs transactivation concept proved to be too simplistic, the developed SEGRAMs were helpful in elucidating various molecular actions of the glucocorticoid receptor, but have also raised many novel questions. We discuss lessons learned from recent mechanistic studies of selective glucocorticoid receptor modulators. This is approached by analyzing recent experimental insights in comparison with knowledge obtained using mutant GR research, thus clarifying the current view on the SEGRAM field. These insights also contribute to our understanding of the processes controlling glucocorticoid-mediated side effects as well as glucocorticoid resistance. Our perspective on non-steroidal SEGRAs and SEGRMs considers remaining opportunities to address research gaps in order to harness the potential for more safe and effective glucocorticoid receptor therapies.

The triterpene echinocystic acid and its 3-O-glucoside derivative are revealed as potent and selective glucocorticoid receptor agonists

“…However, side effects such as HPA axis suppression arise from GR transrepressional activities, whereas others such as osteoporosis are mediated by both transactivation and transrepression (Sundahl et al, 2015). Accordingly, there is a significant need for potent selective steroidal or non-steroidal glucocorticoid receptor agonist (SEGRAs) or modulators (SEGRMs) as effective as classic GCs, but with a reduced side effect profile (Kleiman and Tuckermann, 2007;De Bosscher et al, 2010;Vandevyver et al, 2013).…”

“…Accordingly, there is a significant need for potent selective steroidal or non-steroidal glucocorticoid receptor agonist (SEGRAs) or modulators (SEGRMs) as effective as classic GCs, but with a reduced side effect profile (Kleiman and Tuckermann, 2007;De Bosscher et al, 2010;Vandevyver et al, 2013). These compounds can bind to the same or to different GCs binding sites in Cterminal of the ligand binding domain (LBD) of GR and may cause different GR conformational changes (Sundahl et al, 2015).…”

Animal models to explore the effects of glucocorticoids on skeletal growth and structure

“…GCs may lead to some localized changes in bone strength that are similar to other causes of osteoporosis, but they also display some unique effects which explains why GC exposure is associated with a higher risk of fracture at equivalent BMD and hence reinforcing the need for an appropriate animal model to specifically investigate GIO (Lane 2005, Xia et al 2010. In addition, the search continues to find selective GR agonists that possess the anti-inflammatory benefits of traditional GCs without the associated adverse effects (Sundahl et al 2015). Suitable pre-clinical models are also vital to this process.…”

Update on treatment of polymyalgia rheumatica

“…DAGR bind to the GC receptor inducing a cytosolic GC receptor/protein interaction which results in so-called trans-repression mediating immunosuppression. In contrast, DNA binding and trans-activation leads to adverse events, though this effect is much less with DAGRs (45). Another interesting development is liposomal GCs.…”