Selective glucocorticoid receptor modulator

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.

History

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.