Vascular Biology & Therapeutics and Yale Cardiovascular Research Center Seminar present "Endothelial Cell Transcription: from Developmental Genetics to Drug Repurposing" by Mathias Francois, PhD

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Abstract: Modulation of transcription factor (TF) activity holds great promise for the development of targeted therapeutics, because these proteins act at the point of convergence for cell signaling and directly orchestrate gene expression. Many transcription factors depend on interactions with partner proteins for their activity, and so attempts to develop therapeutics have focused on disrupting interactions critical for nuclear shuttling, post-translational modification or dimerization. However, isolating and targeting one specific interaction is often insufficient to generate a biological effect, due to redundancies in regulatory pathways in which transcription factors are involved. During the presentation, I will show a novel molecular strategy that is efficient to interfere with the SOX18 TF activity to perturb vascular outgrowth in pre-clinical model systems. Further, using this new strategy we have identified a FDA-approved drug that has been successfully repurposed to manage two rare vascular disorders in Human. Our work provides a proof of therapeutic utility for a novel strategy to inhibit transcription factor activity, through interference with a node of protein-protein interactions, re-establishing transcription factors as a viable class of molecular targets for small molecules in therapeutic settings.