Translational Biopharmaceutics for Proteolysis Targeting Chimeras (PROTACs)

The vision for this project is to create porosity between King's College London and AstraZeneca to facilitate the development of novel medicines that require advanced drug delivery systems. A senior academic from the Institute of Pharmaceutical Science, Professor Ben Forbes, will embed in projects within AstraZeneca to assess drug delivery strategies and technological innovations implemented during early phase development to assist progression to first-in-man studies.

The principal focus of the project will be to support the development of PROteolysis Targeting Chimeras (PROTACs). PROTACS are bifunctional molecules designed to target proteins for degradation by engaging the ubiquitin proteasome system. A key benefit of this drug modality is the ability to modulate disease-causing intracellular target proteins that are undruggable with small-molecule inhibitors. PROTAC pharmacology dictates three basic structural features: 1) a ligand "warhead" binding the target protein-of-interest, 2) a ligand "warhead" binding ubiquitin E3 ligase and 3) a "linker" to connect the two warheads. These features give a lower molecular weight limit of ~700 Da for this class of chemical which confers poor oral bioavailability. Standard methods for developing drugs to the clinic have proved unsuccessful for PROTACs.

The key objectives of the project are to address knowledge gaps and build capability for AstraZeneca in the areas of (i) mechanistic approaches for modelling oral absorption of PROTACs, (ii) mechanistic approaches for modelling the impact of oral enabling formulations/absorption enhancers on drug absorption, (iii) development of new in vitro solubility and permeability screening assays to reduce dependency on non-clinical PK studies, (iv) optimised simulation models to predict drug absorption, and (vi) a framework for assessing drug developability and formulation strategy for early phase clinical studies.

This project is innovative in enabling cross-sector porosity between academia and industry for scientists with biopharmaceutics expertise in both locations. This will permit exchange of knowledge and skills, including project specific skills, knowledge transfer and career development for these scientists. The project is designed to intensify knowledge exchange between the biomedical industry and academia in UK in the area of biopharmaceutics where gaps in knowledge hinder the commercial realisation and translation to the clinic of important, but difficult-to-deliver new therapeutic entities. We aim to develop a framework for drug development and case studies that will boost the confidence and ability of the Biomedical Sciences sector to develop 'difficult' drug candidates which will help the UK economy by increasing productivity