PhD defence C. (Chunlong) Zhao
When: | Tu 22-10-2024 11:00 - 12:00 |
Where: | Academy Building |
Design, synthesis, and biological evaluation of PROTACs targeting histone deacetylases
Development of small molecule modulators for proteins has proven to be successful in drug discovery in the past several decades. However, for a significant number of drug targets, classical occupancy-based approaches are not feasible. For example, proteins without well-defined or with shallow binding pockets are considered “undruggable” targets, because of the lack of high affinity small molecule binders. Additionally, besides enzymatic activities, some proteins also have non-enzymatic functions, which cannot be targeted by traditional high affinity small molecules that bind to the enzymatic active site. Due to the limitations of molecules with an occupancy-based mode of action, novel drug modalities have recently gained importance in drug research, discovery, and development. New drug modalities that trigger targeted protein degradation, such as proteolysis-targeting chimeras (PROTACs), have been attracting intense attention in recent drug discovery. In this thesis, we aim to explore the druggability of the non-enzymatic functions of histone deacetylases (HDACs), especially for HDAC3 and HDAC8 via the PROTAC strategy. We have developed HDAC3 and HDAC8 PROTACs to block both the enzymatic and non-enzymatic functions of HDAC3 and HDAC8. We also utilize these PROTACs to investigate HDAC functions in disease models to increase our understanding of their mode of action.