Unit:
Faculty of MedicineLibrary of the School of Health Sciences
Dissertation committee:
Παρασκευή Μουτσάτσου – Λαδικού, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Μιχαήλ Αλέξης, Ομότιμος Ερευνητής, ΙΧΒ, Εθνικό Ίδρυμα Ερευνών
Δήμητρα Μήτσιου Ερευνήτρια B', ΙΧΒ, Εθνικό Ίδρυμα Ερευνών
Ευανθία Κασσή, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Ευθυμία Κιτράκη, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Σταυρούλα Κουλοχέρη , Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Άννα-Μαρία Ψαρρά, Αναπληρώτρια Καθηγήτρια, Τμήμα Βιοχημείας και Βιοτεχνολογίας, Πανεπιστήμιο Θεσσαλίας
Original Title:
Ανάπτυξη επιλεκτικών μη στεροειδών αγωνιστών του υποδοχέα των γλυκοκορτικοειδών και αποτίμηση της αντικαρκινικής δράσης τους
Translated title:
Development of selective non-steroidal glucocorticoid receptor agonists and evaluation of their anticancer activity
Summary:
Glucocorticoids (GCs) are widely used as potent anti-inflammatory drugs; however, GC therapy is often accompanied by adverse side effects. The anti-inflammatory action of GCs is exerted through the glucocorticoid receptor (GR) in part by antagonizing the pro-inflammatory nuclear factor κB (NF-κB) whereas the majority of side effects are assumed to be mediated by transactivation of GR target genes. Development of novel non-steroidal selective GR agonists (SEGRA) favoring transrepression of NF-κB target genes over transactivation of genes associated with undesirable effects could improve the clinical performance of GCs.
In the present study we set out to identify non-steroidal selective GR agonists utilizing a virtual screening approach of Ambinter library (7.8 million compounds). Two structurally similar hits (1,3-benzothiazole analogs) were identified that bind to GR, induce its translocation to the nucleus, do not mediate transactivation of GR target genes, whereas partially repress a number of pro-inflammatory NF-Bκ target genes, in a GR-dependent manner. The discovered 1,3-benzothiazole analogs introduce a new class of genuine SEGRA. Evaluation of the action of the new hit compounds as well as of classical GR agonists in specialized models of cancer cells with hyperactivated NF-κB did not reveal anticancer activity.
Compound AZD9567, a non-steroidal selective GR agonist, was used in order to study the mechanisms underlying the function of SEGRA. AZD9567 was shown to act as a partial agonist of GR capable of substituting for circulating hydrocortizone at pharmacologically relevant concentrations. Identification of the global transcriptomic profile of compound AZD9567 in mouse macrophages showed that AZD9567, although it does not mediate some of the known actions of glucocorticoids (cell death, fat cell differentiation), mediates many of their classical actions (regulation of circadian rhythm, leukocyte differentiation, inflammatory response) but also different actions (cytokine production, defense response, immune response). Under conditions that elicit an inflammatory response, the anti-inflammatory action of AZD9567 is mediated, at least in part, by the same principal mechanisms involved in the anti-inflammatory activity of classical glucocorticoids. Finally, under the same conditions, compound AZD9567 regulates a set of new genes mainly related to biosynthesis, metabolism and modifications of (macro)molecules. In conclusion, compound AZD9567 mediates common but also different biological processes compared to classical glucocorticoids both in the absence and presence of an inflammatory response and its different transcriptomic profile may account for its improved therapeutic effect.
Main subject category:
Health Sciences
Keywords:
Glucocorticoid receptor, Selective agonists, Dexamethasone, AZD9567, Anti-inflammatory action, Transcriptomic profile
