Abstract

Protein-protein interactions (PPIs) mediate all cellular signalling processes, play a central role in disease and represent the majority of bimolecular interactions with estimates for the PPI interactome as high as ~650,000 pairwise interactions. Developing chemical probes to interrogate cell-signalling pathways represents a significant challenge of immense biochemical and medical importance. However, methods to target intracellular (PPIs) using small molecules are not well established, given that they must cover 800-1100Å2 of a protein surface and complement the discontinuous projection of hydrophobic and charged domains over a flat or moderately convex surface. This presentation will highlight our latest efforts to develop enabling methods for the design of PPI inhibitors. Inhibitors of PPIs involved in oncology (e.g. p53/hDM2, NOXA-B/Mcl-1, HIF-1α/p300) will be discussed.