DiscussionIdentification of direct modulators of transcription factor protein-protein interactions is a key challenge for ligand discovery that promises to significantly advance current approaches to cancer therapy. Here, we report a genetically encoded high-throughput screening platform for the identification of protein-protein interaction inhibitors. This platform has been used for the identification of compounds capable of disrupting the association and assembly of protein complexes, including compounds that disrupt metabolite-sensing transcription factors. The uncovered inhibitors have served as valuable tools that have allowed better understanding of the link between tumour metabolism and the altered gene expression of cancer cells. These compounds also form the starting point for the development of therapeutic compounds that target key protein-protein interactions in disease.