Project ID iCASE2024_05_CM-HD

ThemeCM-HD

Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, Institute of Pharmaceutical ScienceWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, Institute of Pharmaceutical ScienceWebsite

Additional Supervisor Dr Magda Swedrowska & Dr Sam Nash

Partner AstraZeneca

Measuring permeability to understand the mechanisms and predict absorption of PROTACs following oral administration

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

Representative Publications

Co-1A
1. Procopiou, George, Paul JM Jackson, Daniella di Mascio, Jennifer L. Auer, Chris Pepper, Khondaker Miraz Rahman, Keith R. Fox, and David E. Thurston. “DNA sequence-selective GA cross-linking ADC payloads for use in solid tumour therapies.” Communications Biology 5, no. 1 (2022): 741. https://doi.org/10.1038/s42003-022-03633-0.
2. Corcoran, David B., Thomas Lewis, Kazi S. Nahar, Shirin Jamshidi, Christopher Fegan, Chris Pepper, David E. Thurston, and Khondaker Miraz Rahman. “Effects of systematic shortening of noncovalent C8 side chain on the cytotoxicity and NF-κB inhibitory capacity of pyrrolobenzodiazepines (PBDs).” Journal of Medicinal Chemistry 62, no. 4 (2019): 2127-2139. https://doi.org/10.1021/acs.jmedchem.8b01849.
3. Kelly, J.R., Martini, S., Brownlow, N., Joshi, D., Federico, S., Jamshidi, S., Kjaer, S., Lockwood, N., Rahman, K.M., Fraternali, F. and Parker, P.J., 2020. The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition. Nature communications, 11(1), p.1396. https://doi.org/10.1038/s41467-020-15163-6

Co-1B
1. “Label-free study of intracellular glycogen level in metformin and resveratrol-treated insulin-resistant HepG2 by live-cell FTIR spectroscopy”, A. Poonprasartporn and K. L. Andrew Chan*, Biosensors and Bioelectronics, 2022, doi.org/10.1016/j.bios.2022.114416
2. “In vitro Fourier transform infrared spectroscopic study of the effect of glycerol on the uptake of beclomethasone dipropionate in living respiratory cells” W. Terakosolphan, A. Altharawi, A. Poonprasartporn, R. D. Harvey, B. Forbes and K. L. Andrew Chan*, 2021, International Journal of Pharmaceutics, DOI: 10.1016/j.ijpharm.2021.121118
3. “Towards identifying the mode of action of drugs using live-cell FTIR spectroscopy”, Ali Altharawi, K. M. Rahman and K. L. Andrew Chan*, 2019, Analyst, doi.org/10.1039/C8AN02218F