Investigating efflux transporter liabilities of targeted protein degraders to enable their application for the treatment of neurodegenerative diseases

Collectively, over 1 million people have Alzheimer’s and Parkinson’s Disease in the UK. Both diseases are progressive and have no cure. The chemistry currently used to treat these diseases accesses specific protein targets in the brain and typically, attempts to block them. These approaches have had a high clinical failure rate due to not working as hoped in humans. Targeted Protein Degradation is an emerging alternative method that uses chemistry to remove, rather than simply block, the proteins that cause these diseases from neuron cells in the brain. In fact, the first human clinical trial for a targeted protein degrader drug was initiated for Parkinson’s Disease in 2024. However, in order to be effective, these treatments must be designed and optimised to allow them to enter the brain, via a barrier between our blood and our brain. Currently, we do not have methods to test large numbers of prototype treatments/drug compounds to understand how this barrier may be stopping them from entering the brain and to develop design rules for how future targeted protein degradation therapies can most efficiently access the brain. This project will address this question by developing a series of new biological tests in cells that inform on which prototype compounds are more likely to enter the brain, increasing chances of successful discovery of effective treatments and reducing the extent of animal testing required.