Selective glucocorticoid receptor modulators (SEGRMs) and selective glucocorticoid receptor agonists (SEGRAs) formerly known as dissociated glucocorticoid receptor agonists (DIGRAs) are a class of experimental drugs designed to share many of the desirable anti-inflammatory, immunosuppressive, or anticancer properties of classical glucocorticoid drugs but with fewer side effects such as skin atrophy. Although preclinical evidence on SEGRAMs’ anti-inflammatory effects are culminating, currently, the efficacy of these SEGRAMs on cancer are largely unknown.
Selective glucocorticoid receptor agonists (SEGRAs) are historically and typically steroidal in structure while selective glucocorticoid receptor modulators (SEGRMs) are typically nonsteroidal. The combined abbreviation of selective glucocorticoid receptor agonist and modulator is SEGRAM. A number of such ligands have been developed and are being evaluated in preclinical and clinical testing.
SEGRAMs achieve their selectivity by triggering only a subset the glucocorticoid receptor mechanisms of action.
Synthetic steroids with SEGRA-like properties were already discovered in the late 1990s. During the 2000s, many potential SEGRAMs were synthesized, most of them having nonsteroidal structures. In in vitro studies in cellular models these SEGRAM molecules bind to the glucocorticoid receptor with an affinity similar to dexamethasone, a potent glucocorticoid, and with an ability to repress the production of inflammatory mediators such as interleukin 6 and prostaglandin E2. Moreover, in vitro a particular SEGRAM can promote apoptosis in prostate cancer and leukemia.
In vivo studies in mice and rats showed that a topically administered SEGRAM inhibited peroxidase activity and formation of oedema, both indicators of anti-inflammatory activity, comparably to prednisolone. Systemic administration in mice or rats indicate that SEGRAMs can diminish acute infections, rheumatoid arthritis, asthma and colitis.
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In the field of molecular biology, transrepression is a process whereby one protein represses (i.e., inhibits) the activity of a second protein through a protein-protein interaction. Since this repression occurs between two different protein molecules (intermolecular), it is referred to as a trans-acting process. The protein that is repressed is usually a transcription factor whose function is to up-regulate (i.e., increase) the rate of gene transcription. Hence the net result of transrepression is down regulation of gene transcription.
In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the expression of specific genes thereby controlling the development, homeostasis, and metabolism of the organism. Nuclear receptors bind directly to DNA regulating the expression of adjacent genes; hence these receptors are classified as transcription factors.
The glucocorticoid receptor (GR, or GCR) also known as NR3C1 (nuclear receptor subfamily 3, group C, member 1) is the receptor to which cortisol and other glucocorticoids bind. The GR is expressed in almost every cell in the body and regulates genes controlling the development, metabolism, and immune response. Because the receptor gene is expressed in several forms, it has many different (pleiotropic) effects in different parts of the body. When glucocorticoids bind to GR, its primary mechanism of action is the regulation of gene transcription.
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