Design and development of glucocorticoid receptor modulators.

Area of Science:

• Pharmacology
• Molecular Biology
• Drug Development

Background:

• Synthetic glucocorticoids (GCs) are potent anti-inflammatory agents but are associated with significant adverse effects (AEs).
• Initially, the anti-inflammatory effects and AEs of GCs were attributed to distinct mechanisms of the glucocorticoid receptor (GR): transrepression and transactivation, respectively.
• Emerging evidence suggests a more complex mechanism of GC action, prompting the development of novel GR modulators (GRMs).

Purpose of the Study:

• To review the current understanding of GR-mediated gene regulation.
• To discuss the transrepression-transactivation profile of GCs concerning their efficacy and AEs.
• To highlight advancements in developing novel GRMs, including selective GR agonists and modulators (SEGRAMs).

Main Methods:

• Review of existing literature on GR-mediated gene regulation.
• Analysis of the transrepression-transactivation profiles of GCs and GRMs.
• Examination of technological advances in the design and development of novel GRMs.

Main Results:

• The distinction between GR transrepression and transactivation provides a framework for designing GRMs with improved safety profiles.
• Novel GRMs are being developed to selectively modulate GR activity, aiming to separate anti-inflammatory benefits from AEs.
• Vamorolone, a dissociated steroid GRM, gained marketing approval in 2024, validating the strategy of altering the GR transrepression-transactivation balance.

Conclusions:

• Modulating the GR transrepression-transactivation balance is a viable strategy for developing safer anti-inflammatory drugs.
• Technological innovations are crucial for the design and development of next-generation GRMs.
• Further research into the mechanisms of action of novel GRMs is essential for optimizing their therapeutic potential.