Proteolysis-targeting chimeras (PROTACs) are an emerging new therapeutic class of drugs with the potential to open “drug target space” not accessible to conventional small molecule drugs. PROTACs have potential applications in many diseases, with their potential as anticancer medicines at the forefront of clinical development. PROTACs are a complex medicines, being large molecules with three key components, a proteolytic unit, a linker and a targeting ligand. Their pharmaceutical development for translation to the clinic requires an understanding of the barriers to absorption after oral administration. The aim of this project is to develop novel and optimised assay methodology that will enable the permeability of PROTACs to be investigated in vitro to understand their unusual oral drug absorption properties. The techniques that will be learnt during the PhD include live cell FTIR, radiochemistry to label model PROTAC molecules, cell culture and the application of epithelial cell-based drug permeability models, data analysis to develop in vitro-in vivo correlations for drug absorption and in silico mechanistic physiologically-based biopharmaceutics modeling. The PhD project is designed such that FTIR will be developed continuously over the four years of the project with the technique being established and validated initially, then used to study permeability mechanisms and the effect of intestinal conditions or formulation excipients. In parallel, model PROTACs will be radiolabelled and used to optimise an in vitro permeability assay (Year 1), this assay will be deployed to perform in vitro-in vivo correlations (Year 2). These in vitro data will be used as inputs for development of a physiologically-based biopharmaceutics model (year 3) which will be validated with proof-of-concept experiments in the final year.
Third Supervisor: Prof Ben Forbes