Abstract
Exogenous glucocorticoids are widely used in the clinic for the treatment of inflammatory disorders and hematological cancers. Unfortunately, their use is associated with debilitating side effects, including hyperglycemia, osteoporosis, mood swings, and weight gain. Despite the continued efforts of pharma as well as academia, the search for so-called selective glucocorticoid receptor modulators (SEGRMs), compounds with strong anti-inflammatory or anti-cancer properties but a reduced number or level of side effects, has had limited success so far. Although monoclonal antibody therapies have been successfully introduced for the treatment of certain disorders (such as anti-TNF for rheumatoid arthritis), glucocorticoids remain the first-in-line option for many other chronic diseases including asthma, multiple sclerosis, and multiple myeloma. This perspective offers our opinion on why a continued search for SEGRMs remains highly relevant in an era where small molecules are sometimes unrightfully considered old-fashioned. Besides a discussion on which bottlenecks and pitfalls might have been overlooked in the past, we elaborate on potential solutions and recent developments that may push future research in the right direction.
Highlights
Glucocorticoids (GCs) are endogenous steroidal hormones involved in metabolism, stress, development, and immunity [1]
We offer our view on a number of bottlenecks and pitfalls that might have hampered research progress in the past and elaborate on which new developments and insights could help overcome these issues
AntiTNF therapy has been associated with a 250% increase in the occurrence of tuberculosis [46]. These therapies have been reported to trigger multiple sclerosis (MS) and other demyelinating conditions [47,48,49,50]. This is in line with the reported disease worsening in patients with pre-existing MS in clinical trials for Lenercept and cA2, two types of anti-tumor necrosis factor (TNF) therapy [51, 52]
Summary
Glucocorticoids (GCs) are endogenous steroidal hormones involved in metabolism, stress, development, and immunity [1]. Dimer-mediated gene activation contributes to the anti-inflammatory effects of GCs via the upregulation of anti-inflammatory genes such as glucocorticoid-induced leucine zipper (GILZ) and dual specificity phosphatase (DUSP1) [10] This helps explaining why GRdim mice show increased sensitivity to acute inflammation such as septic shock [11]. This is in line with the reported disease worsening in patients with pre-existing MS in clinical trials for Lenercept and cA2, two types of anti-TNF therapy [51, 52] Beside such side effects, monoclonal therapies are generally very expensive, laying a huge burden on health care systems, which will only increase with aging populations in western countries. Croton oil-induced irritant contact dermatitis in mice and rats Dinitrofluorobenzene (DNFB)-induced allergic contact dermatitis in mice and rats Dry eye model in rabbits Paracentesis model in rabbits Ovalbumin-induced allergic conjunctivitis in guinea pigs Compound 48/80-induced wheal and erythema skin inflammation in beagles
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