Supervisors info:
Εμμανουήλ Μικρός, Καθηγητής, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Summary:
Over the last century, the ever-increasing interest in the study of epigenetics has contributed immensely to our understanding of the development of various diseases. Epigenetic readers and erasers, such as the Bromodomain and Extra Terminal (BET) subfamily of bromodomains and Histone deacetylases (HDAC), respectively, have emerged as highly promising drug targets. Both play a crucial role in multiple cellular processes and thus their abnormal expression or function has been implicated in a plethora of pathologies, which in many cases are common for the two classes, including multiple cancer types, inflammatory diseases and viral infections. As a result, concerted efforts have led to the identification of diverse potent BET and HDAC inhibitors, which however are not void of issues, including limited or short-lived efficacy and toxicity concerns. More advanced approaches have been developed, including the design of dual BET/HDAC inhibitors to combat these limitations, with promising results.
The chemical diversity of the hitherto identified inhibitors perplexes the selection of the optimal individual scaffolds for the design of dual inhibitors. The objective of this study is the structural and binding characterization of various inhibitor scaffolds aiming to determine the ideal candidates which can be most efficiently combined into a compound that will inhibit both targets simultaneously. An initial screening assay based on differential scanning fluorimetry was performed, which revealed numerous hit-compounds worth further evaluation. Afterwards, these preliminary results were corroborated via isothermal titration calorimetry experiments, providing important information about the affinity of the compounds and the thermodynamic aspect of the binding. Lastly, X-ray crystallography was utilized to obtain elucidating structural data about the binding mode of the inhibitors. Acquiring this significant insight and a complete overview of the binding properties of each compound-scaffold is bound to be extremely valuable in future drug discovery attempts for these attractive drug targets and the battle against the ailments their deregulation can trigger.
Keywords:
bromodomain, BET, histone deacetylase, HDAC, epigenetics, dual inhibitor, structural biology
