Laboratory of Experimental Cancer Research (LECR), Department of Radiation Oncology & Experimental Cancer Research, Ghent University, Gent, Belgium.
Department for Molecular Biomedical Research, VIB, Gent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Gent, Belgium.
Pharmacol Ther. 2015 Aug;152:28-41. doi: 10.1016/j.pharmthera.2015.05.001. Epub 2015 May 6.
Glucocorticoids remain the frontline treatment for inflammatory disorders, yet represent a double-edged sword with beneficial therapeutic actions alongside adverse effects, mainly in metabolic regulation. Considerable efforts were made to improve this balance by attempting to amplify therapeutic beneficial anti-inflammatory actions and to minimize adverse metabolic actions. Most attention has focused on the development of novel compounds favoring the transrepressing actions of the glucocorticoid receptor, assumed to be important for anti-inflammatory actions, over the transactivating actions, assumed to underpin the undesirable actions. These compounds are classified as selective glucocorticoid receptor agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). The latter class is able to modulate the activity of a GR agonist and/or may not classically bind the glucocorticoid receptor ligand-binding pocket. SEGRAs and SEGRMs are collectively denominated SEGRAMs (selective glucocorticoid receptor agonists and modulators). Although this transrepression vs transactivation concept proved to be too simplistic, the developed SEGRAMs were helpful in elucidating various molecular actions of the glucocorticoid receptor, but have also raised many novel questions. We discuss lessons learned from recent mechanistic studies of selective glucocorticoid receptor modulators. This is approached by analyzing recent experimental insights in comparison with knowledge obtained using mutant GR research, thus clarifying the current view on the SEGRAM field. These insights also contribute to our understanding of the processes controlling glucocorticoid-mediated side effects as well as glucocorticoid resistance. Our perspective on non-steroidal SEGRAs and SEGRMs considers remaining opportunities to address research gaps in order to harness the potential for more safe and effective glucocorticoid receptor therapies.
糖皮质激素仍然是治疗炎症性疾病的一线药物，但它是一把双刃剑，具有治疗作用的同时也有不良反应，主要是在代谢调节方面。人们做了大量努力来改善这种平衡，试图放大治疗有益的抗炎作用，减少不良的代谢作用。大多数注意力都集中在开发新型化合物上，这些化合物有利于糖皮质激素受体的转录阻遏作用，被认为对抗炎作用很重要，而不是转录激活作用，后者被认为是产生不良作用的基础。这些化合物被归类为选择性糖皮质激素受体激动剂（SEGRAs）或选择性糖皮质激素受体调节剂（SEGRMs）。后者能够调节 GR 激动剂的活性，或者可能不经典地结合糖皮质激素受体配体结合口袋。SEGRAs 和 SEGRMs 统称为 SEGRAMs（选择性糖皮质激素受体激动剂和调节剂）。尽管这种转录阻遏与转录激活的概念被证明过于简单化，但开发的 SEGRAMs 有助于阐明糖皮质激素受体的各种分子作用，但也提出了许多新的问题。我们讨论了从最近的选择性糖皮质激素受体调节剂的机制研究中吸取的经验教训。这是通过分析最近的实验见解，并与使用突变 GR 研究获得的知识进行比较来实现的，从而阐明了目前对 SEGRAM 领域的看法。这些见解也有助于我们理解控制糖皮质激素介导的副作用以及糖皮质激素抵抗的过程。我们对非甾体 SEGRAs 和 SEGRMs 的看法考虑了利用研究空白的机会，以利用更安全有效的糖皮质激素受体治疗的潜力。
