Activity-Directed Discovery of Inhibitors of the p53/Human-MDM2 Protein–Protein Interaction

Methods for the discovery of bioactive small molecules are a constant source of innovation in drug discovery. Typically, medicinal chemists discover molecules in design-make-test cycles and invest equal resources into each molecule regardless of biological function. New and emerging workflows for the rapid discovery of bioactive small molecules aim to redistribute resources to high value, active small molecules. This thesis focuses on developing a discovery workflow that invests resources exclusively in high-value, active molecules, and circumvents limitations of traditional discovery workflows. Chapter 1 gives an overview of modern drug discovery practices and focuses on emerging methods for the integrated and high-throughput discovery of bioactive small molecules. Chapter 1 also outlines the biological and medicinal chemistry of the p53/MDM2 protein–protein interaction, and proposes the PPI as a target for activity-directed small molecule discovery. Chapter 2 describes the development of a computational map for the selection of catalysts in high-throughput reaction arrays. Principal component analysis of a library of 48 DFT-optimised rhodium(II) catalysts was used to build the map from a collection of bespoke computational descriptors. The map was compared to a variety of experimental data sources and found to be a useful tool for interpreting reaction outcomes. Chapter 3 describes the design and implementation of two high-throughput reaction arrays for the activity-directed discovery of inhibitors of the p53/MDM2 protein–protein interaction. 346 microscale reactions were performed and seven products were isolated from the scale-up of hit reaction mixtures. Chapter 4 describes the characterisation of hit molecules identified from the activity-directed synthesis workflow. The products were tested in orthogonal biological assays and four distinct series were found to have low micromolar inhibitory activity of the p53/MDM2 protein–protein interaction. Similarity analysis also demonstrated that the products have promising ligand efficiencies and that the products can provide new starting points for drug discovery.