PhD defence C. (Chunlong) Zhao

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.