Discovering how the cell orchestrates the expression of all of its genes is fundamental to biology and therapy development. A single transcription factor can have a multitude of effects and regulate multiple genes. This versatility of activity is thought to be mediated by different protein-protein interactions. These protein-protein interactions also offer a new avenue for the pharmacological modulation of transcription factor activity, which has proven to be a challenging endeavour using standard drug discovery approaches centred on blocking protein/DNA binding or interfering with post-translational modifications.
In this study we show that SOX18, a transcription factor involved in embryonic lymphatic vasculature formation and neolymphangiogenesis during cancer development, can associate with multiple protein partners. Using truncations, we propose a comprehensive map of the protein binding domains, revealing the existence of different binding sites. Using pathological mutants of SOX18 associated with lymphatic diseases, such as Hypotrichosis-Lymphedema-Telangiectasia (HLT), we show specific loss of interactions and correlate these observations with differences in phenotype.
Using a focused library of small molecules, we are able to show that different protein pairs can be targeted and we propose the first Structure-Activity Relationship studies, leading the way to the development of inhibitors of specific protein-protein interactions. This enabled us to understand the molecular mode of action of a compound currently used in clinic to treat HLT patients. Finally, we show that one of our new small molecules is able to prevent development of metastasis in a mouse cancer model, validating the value of targeting complexes of transcription factors.
These studies open up a new understanding of pathological phenotypes and can help decipher a new road for anti-cancer drug discovery.