Discovery of Compound A : a selective activator of the glucocorticoid receptor with anti-inflammatory and anti-cancer activity

dc.contributor.authorLesovaya, Ekaterinaen_ZA
dc.contributor.authorYemelyanov, Alexanderen_ZA
dc.contributor.authorSwart, Amanda C.en_ZA
dc.contributor.authorSwart, Pieteren_ZA
dc.contributor.authorHaegeman, Guyen_ZA
dc.contributor.authorBudunova, Irinaen_ZA
dc.date.accessioned2016-08-30T12:34:53Z
dc.date.available2016-08-30T12:34:53Z
dc.date.issued2015
dc.descriptionCITATION: Lesovaya, E. et al. 2015. Discovery of Compound A : a selective activator of the glucocorticoid receptor with anti-inflammatory and anti-cancer activity. Oncotarget, 6(1):30730-30744, doi:10.18632/oncotarget.5078.
dc.descriptionThe original publication is available at www.impactjournals.com/oncotarget
dc.description.abstractGlucocorticoids are among the most effective anti-inflammatory drugs, and are widely used for cancer therapy. Unfortunately, chronic treatment with glucocorticoids results in multiple side effects. Thus, there was an intensive search for selective glucocorticoid receptor (GR) activators (SEGRA), which retain therapeutic potential of glucocorticoids, but with fewer adverse effects. GR regulates gene expression by transactivation (TA), by binding as homodimer to gene promoters, or transrepression (TR), via diverse mechanisms including negative interaction between monomeric GR and other transcription factors. It is well accepted that metabolic and atrophogenic effects of glucocorticoids are mediated by GR TA. Here we summarized the results of extensive international collaboration that led to discovery and characterization of Compound A (CpdA), a unique SEGRA with a proven “dissociating” GR ligand profile, preventing GR dimerization and shifting GR activity towards TR both in vitro and in vivo. We outlined here the unusual story of compound’s discovery, and presented a comprehensive overview of CpdA ligand properties, its anti-inflammatory effects in numerous animal models of inflammation and autoimmune diseases, as well as its anti-cancer effects. Finally, we presented mechanistic analysis of CpdA and glucocorticoid effects in skin, muscle, bone, and regulation of glucose and fat metabolism to explain decreased CpdA side effects compared to glucocorticoids. Overall, the results obtained by our and other laboratories underline translational potential of CpdA and its derivatives for treatment of inflammation, autoimmune diseases and cancer.en_ZA
dc.description.urihttp://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=5078
dc.description.versionPublisher's version
dc.format.extent15 pages
dc.identifier.citationLesovaya, E. et al. 2015. Discovery of Compound A : a selective activator of the glucocorticoid receptor with anti-inflammatory and anti-cancer activity. Oncotarget, 6(1):30730-30744, doi:10.18632/oncotarget.5078.
dc.identifier.issn1949-2553 (online)
dc.identifier.otherdoi:10.18632/oncotarget.5078
dc.identifier.urihttp://hdl.handle.net/10019.1/99512
dc.language.isoen_ZAen_ZA
dc.publisherImpact Journals
dc.rights.holderImpact Journals
dc.subjectCompound Aen_ZA
dc.subjectSelective glucocorticoid receptor activator (SEGRA)en_ZA
dc.subjectCanceren_ZA
dc.titleDiscovery of Compound A : a selective activator of the glucocorticoid receptor with anti-inflammatory and anti-cancer activityen_ZA
dc.typeArticleen_ZA
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