Design and synthesis of novel proteomimetic scaffolds for the inhibition of protein-protein interactions.

Proteins are essential parts of living organisms and protein-protein interactions (PPIs) interactions mediate many essential regulatory pathways. As such, PPIs have been implicated in a number of diseased states, however, it is currently unclear how to effectively target them due to the relatively poorly defined surface at the protein interface. When PPIs are mediated by the binding of an α-helix, key interactions usually occur on non-adjacent residues, appearing on the same face of the α-helix, resulting in close interactions. The abundance of this secondary structure in proteins and its relative rigidity provide an ideal basis for the design of synthetic mimics. In this thesis, an account of the design strategies developed to address this problem is provided, and sets the work described herein in context. Previously, the Wilson group developed 3-O-alkylated oligobenzamide (3HABA) scaffolds as potential α-helix mimetics and suitably functionalised trimers were identified as micromolar inhibitors of the p53/hDM2 interaction. To understand more how to develop potent inhibitors of this interaction, a larger library was necessary. This was achieved by generating a library of 3HABA building blocks encompassing a range of natural and unnatural functionalities. Parallel to building the monomer library, development of a general solid phase methodology for deactivated anilines was essential. The course taken was to provide a solution for this challenging technical problem, and to identify the scope of the SPS methodology. Using the developed methodology, libraries of compounds targeting the p53/hDM2 and Mcl-1/NOXA B interactions were synthesised and their biophysical properties evaluated resulting in directions for future library development. To extend the approach to helix mediated PPIs involving more than one face, bifacial scaffolds designed at target the ER/coactivator complex are also described. This works discusses how molecular modelling, initial biophysical testing and docking studies led to second generation ligands with better in silico properties.