Org 214007-0: A Novel Non-Steroidal Selective Glucocorticoid Receptor Modulator with Full Anti-Inflammatory Properties and Improved Therapeutic Index

Abstract

Glucocorticoids (GCs) such as prednisolone are potent immunosuppressive drugs but suffer from severe adverse effects, including the induction of insulin resistance. Therefore, development of so-called Selective Glucocorticoid Receptor Modulators (SGRM) is highly desirable. Here we describe a non-steroidal Glucocorticoid Receptor (GR)-selective compound (Org 214007-0) with a binding affinity to GR similar to that of prednisolone. Structural modelling of the GR-Org 214007-0 binding site shows disturbance of the loop between helix 11 and helix 12 of GR, confirmed by partial recruitment of the TIF2-3 peptide. Using various cell lines and primary human cells, we show here that Org 214007-0 acts as a partial GC agonist, since it repressed inflammatory genes and was less effective in induction of metabolic genes. More importantly, in vivo studies in mice indicated that Org 214007-0 retained full efficacy in acute inflammation models as well as in a chronic collagen-induced arthritis (CIA) model. Gene expression profiling of muscle tissue derived from arthritic mice showed a partial activity of Org 214007-0 at an equi-efficacious dosage of prednisolone, with an increased ratio in repression versus induction of genes. Finally, in mice Org 214007-0 did not induce elevated fasting glucose nor the shift in glucose/glycogen balance in the liver seen with an equi-efficacious dose of prednisolone. All together, our data demonstrate that Org 214007-0 is a novel SGRMs with an improved therapeutic index compared to prednisolone. This class of SGRMs can contribute to effective anti-inflammatory therapy with a lower risk for metabolic side effects.

The Future of Steroid Therapy in Inflammatory Disease

“…Of these Compound A (CpdA) was the earliest to be identified and was first isolated from the Namibian shrub (Salsola tuberculatiformis). This non-steroidal compound when investigated was found to bind atypically to the GR in ligand binding essays but with high affinity, and was thought it may be using different coupling points in the Ligand binding domain of the GR or by inducing a unique conformation of the GR which is not yet understood [20][21][22][23][24].…”

“…Due to improvements in the understanding of GR structure researchers have been able to design better SERMs with improved functionality; one example of this is Org 214007-0 [21]. This was based on the fact that this partial GC agonist it can interact between helix 11 and 12 of the ligand binding domain of the GR a point where co-activator binding takes place at a similar affinity to prednisolone with a maintained in vitro profile of action in several studied cell lines.…”

“…Gene's upregulated as part of this process include MuRF1 which was found not to be upregulated by Org 214007-0 treatment. As such this is a very interesting compound which can be used as a platform to study future SERMs and is being suggested for phase 1 clinical trials in an MS model [21]. Table 1: List of known SGRMs/SERMS and their profile of action [19][20][21][22][23].…”

A ligand-specific kinetic switch regulates glucocorticoid receptor trafficking and function

“…Unfortunately glucocorticoid treatment also carries a wide range of serious side effects including hyperglycaemia and osteoporosis (Canalis et al, 2002). In recent years a significant effort has been made to design dissociative ligands with the anti-inflammatory potency of conventional glucocorticoids, but with a reduced spectrum of side-effects (Lin et al, 2002;Bledsoe et al, 2004;Cerasoli, 2006;Wang et al, 2006;McMaster and Ray, 2007;van Lierop et al, 2012).…”

“…The GR AF1 is the site of various post translational modifications including phosphorylation, both in the presence and absence of ligand. (Wang et al, 2002;Ismaili and Garabedian, 2004;GalliherBeckley et al, 2008). Phosphorylation directs GR function by impacting protein stability and recruitment of specific comodulator proteins such as MED14 (Chen et al, 2006;Chen et al, 2008).…”