Authors

L Lewis¹; S Ward²; J Atack³; W Yu⁴; 
¹ Medicines Discovery Institute, UK;  ² The Medicines Discovery Institute, Cardiff University, UK;  ³ Cardiff University, UK;  ⁴ Medicines Discovery Institute, Cardiff University, UK

Discussion

Neurodegenerative diseases represent a major challenge in drug discovery. These diseases are widespread worldwide and are predicted to become the second most common cause of death in the next 20 years by the world health organization. Tauopathies represent a large portion of these diseases with the most prevalent being Alzheimer’s disease (AD). Other tauopathies include Frontotemporal Dementia (FTD), Progressive Supranuclear Palsy, Chronic Traumatic Encephalopathy, Pick’s disease and Corticobasal syndrome. These tauopathies are caused by the accumulation of the microtubule-associated protein tau. In its disease state the tau protein becomes hyperphosphorylated and aggregates to form higher order structures, such as paired helical filaments (PHFs) and neurofibrillary tangles (NFTs).

Protein aggregates are generally classed as ‘undruggable’ due to the lack of easily identifiable binding sites, which are essential for the use of traditional inhibitor-based drugs. In recent years PROTAC (Proteolysis targeting chimera) technology has shown great promise for the degradation of pathogenic proteins such as tau by utilising the UPS system. In this project, a range of PROTACs containing different tau binders and linkers are explored to assess their permeability and efficacy in various models. This project aims to start the development of brain penetrant PROTACs as therapeutics for tauopathies.