SOX18 transcription factor interactome: Protein‐Protein interaction a new road for anti‐cancer drug discovery

Abstract

Deciphering how transcription factors (TFs) coordinate genes expression is fundamental to understand biological processes and further develop new therapeutic approaches. A single transcription factor has a multiple transcriptional effects that are context‐dependent. This versatility of activity is thought to be mediated by different protein‐protein interactions (PPIs). These PPIs offer a new avenue for the selective 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 a molecular switch of embryonic lymphatic vascular development and neo‐lymphangiogenesis during cancer metastasis, interacts with multiple protein partners specific to endothelial cells. Using a systematic truncation analysis of SOX18 domains, we propose a comprehensive map of the protein binding domains, revealing the existence of different interacting regions specific to subsets of SOX18 interactors. Using mutant forms of SOX18 protein associated with human rare disease Hypotrichosis‐Lymphedema‐Telangiectasia (HLT) we validate domains essential to drive specific SOX18‐dependent PPIs and correlate these variations with phenotypic variations observed in HLT.Using a focused library of small molecules, we are able to show that distinct SOX18 protein partner recruitment can be disrupted. On this basis we propose an initial Structure‐Activity Relationship study, paving the way to the development of specific inhibitors to SOX18‐dependent protein‐protein interactions. This approach has enabled us to better understand the mode of action of a compound currently used in clinic to manage HLT condition. Finally, we show that one of our newly identified SOX18 small molecule inhibitor is able to prevent metastasis in a pre‐clinical model of breast cancer, further validating the value of targeting SOX18‐dependent transcription factor complexes.This work opens up a new molecular strategy to target transcription factor activity and reposition this class of protein as viable drug target.