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.