Selective Glucocorticoid Receptor Modulation

Beyond Traditional Steroids: A New Era of Selective Glucocorticoid Receptor Modulation

Avery Sinclair in Health & Wellness November 2025 • 4 min read.

"Discover how scientists are developing innovative therapies to combat inflammation with fewer side effects, offering hope for millions suffering from chronic conditions."

Inflammatory diseases, including rheumatoid arthritis, psoriasis, inflammatory bowel disease, and asthma, affect hundreds of millions worldwide. As the global population expands and life expectancy increases, the market for anti-inflammatory therapies continues to grow. Glucocorticoids (GCs) like Dexamethasone have long been the cornerstone of treatment, but their chronic use leads to significant side effects such as hyperglycemia, growth arrest, glaucoma, and skin thinning.

Researchers are actively seeking new molecules that enhance the therapeutic benefits of GCs while reducing adverse effects. GCs are lipophilic, allowing them to penetrate cell membranes and bind to glucocorticoid receptors (GRs), primarily located in the cytoplasm. Upon binding, the GR translocates to the nucleus, where it executes its anti-inflammatory functions both as a monomeric protein and as a homodimer.

The monomeric form primarily mediates transcriptional transrepression (TR), targeting key inflammatory transcription factors like NF-κB and AP-1. In contrast, the GR homodimer facilitates transactivation (TA), directly controlling DNA-dependent gene expression. While dimeric GR activity transcribes essential anti-inflammatory genes, it also contributes to metabolic side effects. To address these challenges, scientists have been developing Selective GR Agonists and Modulators (SEGRAMs) to fine-tune GR activity.

What is SEDIGRAM and How Can it Help?

Selective Glucocorticoid Receptor Modulation

Researchers have developed Selective Dimerizing GR Agonists and Modulators (SEDIGRAM) through a screening pipeline, focusing on identifying GR agonists that enhance GR homodimerization more effectively than standard glucocorticoids. The SEDIGRAM pipeline includes a reporter gene assay based on a palindromic glucocorticoid responsive element (GRE), which represents GR dimerization in human A549 lung epithelial cells.

The approach is based on a study, published in Nature and other peer reviewed resources, to increase the effectiveness of anti-inflammatory drugs when countering acute inflammatory conditions. Following the initial reporter gene assay, the pipeline involves analysis of endogenous GRE-driven gene expression, a FRET assay to confirm dimerization, and monitoring of in vitro and in vivo anti-inflammatory activity.

Reporter Gene Assay: Measures GR dimerization using a GRE-based reporter gene in A549 cells.
Endogenous Gene Expression: Analyzes the expression of native GRE-driven genes.
FRET Assay: Confirms GR dimerization using Fluorescence Resonance Energy Transfer.
In Vitro Anti-inflammatory Activity: Assesses anti-inflammatory effects in cell cultures.
In Vivo Anti-inflammatory Activity: Monitors anti-inflammatory effects in live animal models.

In a proof-of-principle experiment involving seven candidate compounds, researchers identified Cortivazol and AZD2906 as potentially interesting compounds. These compounds provided strong protection in a mouse model of aggressive TNF-induced lethal inflammation. The screening pipeline for SEDIGRAM helps identify compounds that promote GR dimerization, potentially limiting overwhelming acute inflammatory responses.

What's Next?

The development of SEDIGRAM represents a significant advancement in the quest for safer and more effective anti-inflammatory therapies. By selectively targeting GR dimerization, these novel compounds hold the potential to treat acute and chronic inflammatory conditions while minimizing the debilitating side effects associated with traditional glucocorticoids. Ongoing research and clinical trials will determine the full therapeutic potential of SEDIGRAM, offering new hope for millions suffering from inflammatory diseases. Further studies might solve for the impact of dimerization and decreased plasma clearance.

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This article is based on research published under:

DOI-LINK: 10.1038/s41598-018-31150-w, Alternate LINK

Title: A Screening Assay For Selective Dimerizing Glucocorticoid Receptor Agonists And Modulators (Sedigram) That Are Effective Against Acute Inflammation

Subject: Multidisciplinary

Journal: Scientific Reports

Publisher: Springer Science and Business Media LLC

Authors: Jolien Souffriau, Melanie Eggermont, Sara Van Ryckeghem, Kelly Van Looveren, Lise Van Wyngene, Evelien Van Hamme, Marnik Vuylsteke, Rudi Beyaert, Karolien De Bosscher, Claude Libert

Published: 2018-08-27

Everything You Need To Know

What are glucocorticoids (GCs), and why are researchers looking for alternatives?

Glucocorticoids like Dexamethasone are a cornerstone treatment for inflammatory diseases due to their potent anti-inflammatory effects. However, chronic use leads to significant side effects, including hyperglycemia, growth arrest, glaucoma, and skin thinning. Researchers are actively seeking new molecules to enhance the therapeutic benefits while reducing these adverse effects, such as Selective GR Agonists and Modulators (SEGRAMs).

How do glucocorticoids (GCs) work at a cellular level to reduce inflammation?

Glucocorticoids (GCs) are lipophilic, enabling them to penetrate cell membranes and bind to glucocorticoid receptors (GRs) primarily located in the cytoplasm. Upon binding, the GR translocates to the nucleus, where it executes its anti-inflammatory functions both as a monomeric protein via transcriptional transrepression (TR) and as a homodimer via transactivation (TA). The monomeric form targets inflammatory transcription factors like NF-κB and AP-1, while the dimeric form controls DNA-dependent gene expression, impacting both anti-inflammatory processes and metabolic side effects.

What is SEDIGRAM, and how does it differ from traditional glucocorticoid treatments?

SEDIGRAM, or Selective Dimerizing GR Agonists and Modulators, is a novel approach to anti-inflammatory therapy. Unlike traditional glucocorticoids that can cause widespread side effects due to their broad action on glucocorticoid receptors (GRs), SEDIGRAM aims to selectively enhance GR homodimerization. This selective targeting may allow for the treatment of inflammatory conditions while minimizing the metabolic side effects associated with traditional glucocorticoids by fine-tuning GR activity.

Could you elaborate on the SEDIGRAM screening pipeline and how it identifies promising compounds?

The SEDIGRAM screening pipeline is designed to identify GR agonists that enhance GR homodimerization more effectively than standard glucocorticoids. It starts with a reporter gene assay based on a palindromic glucocorticoid responsive element (GRE) in A549 cells. This is followed by analysis of endogenous GRE-driven gene expression and a FRET assay to confirm dimerization. Finally, the pipeline assesses in vitro and in vivo anti-inflammatory activity. This comprehensive approach ensures that only compounds with the desired selective GR dimerization and anti-inflammatory properties are advanced for further development. Compounds like Cortivazol and AZD2906 have been identified through this pipeline.

What are the potential future implications of SEDIGRAM in treating inflammatory diseases?

SEDIGRAM represents a significant advancement in developing safer and more effective anti-inflammatory therapies. By selectively targeting GR dimerization, these compounds hold the potential to treat acute and chronic inflammatory conditions while minimizing the side effects of traditional glucocorticoids. Future research and clinical trials will further explore SEDIGRAM's therapeutic potential, potentially impacting conditions like rheumatoid arthritis, psoriasis, inflammatory bowel disease, and asthma. Further studies might solve for the impact of dimerization and decreased plasma clearance.