VIB Center for Medical Biotechnology, Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent, Ghent, Belgium.
VIB Center for Medical Biotechnology, Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent, Ghent, Belgium.
Trends Biochem Sci. 2024 May;49(5):431-444. doi: 10.1016/j.tibs.2024.01.012. Epub 2024 Feb 29.
The glucocorticoid receptor (GR) is a major nuclear receptor (NR) drug target for the treatment of inflammatory disorders and several cancers. Despite the effectiveness of GR ligands, their systemic action triggers a plethora of side effects, limiting long-term use. Here, we discuss new concepts of and insights into GR mechanisms of action to assist in the identification of routes toward enhanced therapeutic benefits. We zoom in on the communication between different GR domains and how this is influenced by different ligands. We detail findings on the interaction between GR and chromatin, and highlight how condensate formation and coregulator confinement can perturb GR transcriptional responses. Last, we discuss the potential of novel ligands and the therapeutic exploitation of crosstalk with other NRs.
糖皮质激素受体 (GR) 是治疗炎症性疾病和多种癌症的主要核受体 (NR) 药物靶点。尽管 GR 配体具有疗效，但它们的全身作用会引发多种副作用，限制了长期使用。在这里，我们讨论了 GR 作用机制的新概念和新见解，以帮助确定增强治疗效果的途径。我们详细研究了不同 GR 结构域之间的通讯以及不同配体如何影响这种通讯，并详细介绍了 GR 与染色质之间相互作用的发现，并强调了凝聚物形成和共激活因子限制如何扰乱 GR 的转录反应。最后，我们讨论了新型配体的潜力以及与其他 NR 相互作用的治疗利用。
