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Review
.2020 Sep 24:11:559673.
doi: 10.3389/fendo.2020.559673. eCollection 2020.

Improved Glucocorticoid Receptor Ligands: Fantastic Beasts, but How to Find Them?

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Review

Improved Glucocorticoid Receptor Ligands: Fantastic Beasts, but How to Find Them?

Laura Van Moortel et al. Front Endocrinol (Lausanne)..

Abstract

Exogenous glucocorticoids are widely used in the clinic for the treatment of inflammatory disorders and hematological cancers. Unfortunately, their use is associated with debilitating side effects, including hyperglycemia, osteoporosis, mood swings, and weight gain. Despite the continued efforts of pharma as well as academia, the search for so-called selective glucocorticoid receptor modulators (SEGRMs), compounds with strong anti-inflammatory or anti-cancer properties but a reduced number or level of side effects, has had limited success so far. Although monoclonal antibody therapies have been successfully introduced for the treatment of certain disorders (such as anti-TNF for rheumatoid arthritis), glucocorticoids remain the first-in-line option for many other chronic diseases including asthma, multiple sclerosis, and multiple myeloma. This perspective offers our opinion on why a continued search for SEGRMs remains highly relevant in an era where small molecules are sometimes unrightfully considered old-fashioned. Besides a discussion on which bottlenecks and pitfalls might have been overlooked in the past, we elaborate on potential solutions and recent developments that may push future research in the right direction.

Keywords: GR; SEGRM; assay development; drug discovery; glucocorticoid receptor; glucocorticoids; inflammation; selective GR modulators.

Copyright © 2020 Van Moortel, Gevaert and De Bosscher.

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Figures

Figure 1
Figure 1
Overview of glucocorticoid receptor activity with classic glucocorticoids and selective GR modulators.(A) General action mechanism of the glucocorticoid receptor (GR). Glucocorticoids (GCs) diffuse through the cellular membrane and bind GR. The latter dissociates from its chaperone complex and migrates to the nucleus. There, it dimerizes and binds glucocorticoid response elements (GREs) to upregulate downstream target genes. Monomeric GR also undergoes protein-protein interactions with DNA-bound pro-inflammatory transcription factors (TFs) to downregulate their activity, or it binds directly to the TF response elements (TF-RE).(B) Distinct actions of classic GCs and selective GR modulators (SEGRMs). In contrast to classic GCs, SEGRMs are hypothesized to reduce GR's capacity to dimerize and therefore reduce GRE-mediated transcription. Interference with TF activity is driven via monomeric GR and therefore maintained with SEGRMs.
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