Protein-protein interactions (PPIs) are important therapeutic targets both inside and outside the cell. They are central to all biological processes and are often dysregulated in disease. One such example is the interaction between the pro-inflammatory cytokine IL18 and IL-18 binding protein (IL-18bp). IL-18bp neutralizes IL-18 activity. However, when IL-18 is overexpressed, there is not enough IL-18bp and IL-18 signalling is upregulated, contributing to development of autoimmune diseases1. Another example is the interaction between the final effector of Hippo pathway, Yes associated protein (YAP) and transcription factor TEAD1 that leads to cancer development2. In our current work we are developing high-throughput screening (HTS) assays to identify small molecules that interfere with the interactions between IL18/IL-18bp and YAP/TEAD1. The aim of this work is to identify and optimize small molecules that mimic or inhibit these interactions, ultimately leading to the development of therapeutic compounds. Integral to this work we will preform structural studies to identify interaction sites between prospective compounds and their protein targets using X-ray crystallography. In this study, we have cloned, expressed and purified human recombinant IL-18, IL-18bp, YAP and TEAD1. We confirmed stable complex formation between IL18/IL-18bp and YAP/TEAD1 by Size exclusion chromatography. Then, using Perkin Elmer’s AlphaScreens, we have developed quick, easy and economical assays for HTS of small molecules that disrupt these PPIs. Additionally, we have obtained diffracting crystals of TEAD1 in preparation for structural studies with the prospective inhibitor.