Development of Chemical Probes for Protein-Protein Interactions Inhibition

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Protein-protein interactions (PPIs) control all cellular processes relevant to health and disease.1 Selective inhibition of individual PPIs would thus facilitate both a greater understanding of biological mechanisms; and provide new opportunities for therapeutic intervention. Yet, PPI inhibitors represent a minute fraction of current small molecule drugs, largely because of specific challenges associated with development of inhibitors for these targets. Prior research in our team demonstrated that secondary structure mimetics can be used to inhibit PPIs2 related by structure, however small molecule scaffolds are currently not available to target constellations of side chains relevant to many other PPI classes. We are currently pursuing a major 5-year EPSRC programme (PoPPI) focused on developing tools to facilitate discovery of inhibitors of many PPI classes. Suzanne's PhD project will exploit new computational tools (developed by our partners in Bristol) to design, prepare and evaluate novel small molecule scaffolds for selective inhibition of PPI in cells. The synthesis of these small molecule inhibitors will exploit synthetic approaches that we have developed to target diverse and novel lead-like chemical space.3 Her key objectives will be to identify generic small-molecule scaffolds decorated with two functional groups designed to mimic two hot-spot amino acids at a PPI interface and thus bind to protein targets with reasonable potency. Focussing on novel a-helix mediated targets with therapeutic relevance to oncology and viral conditions, upon successful identification of hits that bind her selected targets, she will further elaborate the scaffolds to mimic a 3rd spot and achieve sufficient potency to inhibit the PPI thus progressing the hit towards chemical probe development and demonstrating that generic scaffolds can be identified for inhibition of protein-protein interactions. Achieving this will contribute to enabling physical sciences methodology to accelerate drug-discovery.Suzanne will gain technical skills in: diversity- and lead-oriented synthesis; and biophysics and evaluation of the cellular function of novel PPI inhibitors.1. Nature Chem., 2013, 5, 161 2. (a) Angew. Chem. Int. Ed., 2015, 54, 2960. (b) Angew. Chem. Int. Ed., 2016, 55, 11096. 3. (a) Org. Biomol. Chem. 2015, 13, 859; (b) Chem. Commun. 2014, 50, 10222