Inhibition of EB3 promotes acute lung injury resolution by promoting the regenerative FOXM1 pathway in endothelial cells

Acute respiratory distress syndrome (ARDS) is the acute onset of non-cardiogenic pulmonary edema, hypoxemia, and respiratory failure. ARDS is frequently caused by bacterial and viral lung infections including the recent SARS-CoV-2. Development of therapeutic approaches to combat ARDS have become an urgent unmet medical need. We address this medical problem by developing a pharmacological treatment for pulmonary vascular leakage, a culprit of alveolar damage and lung inflammation. Our novel therapeutic target is the microtubule accessory factor End Binding protein 3 (EB3), which contributes to pulmonary vascular leakage by amplifying pathological calcium signaling in endothelial cells. Using a structure-activity-relationship approach by Nuclear Magnetic Resonance, we have identified a drug candidate Vascular Therapeutics (VT)-109, an allosteric EB3 inhibitor with optimized physicochemical and biochemical properties. The VT-109 shows marked therapeutic benefits in treating lung injury and inflammation in various models of ARDS including high-volume mechanical ventilation, polymicrobial and SARS-CoV-2 infections. Transcriptome analysis of lung endothelial cells in mice challenged with endotoxin shows that VT-109 upregulates FOXM1 target genes suggesting that the treatment not only mitigates vascular injury but also promotes endothelial cell regeneration by activating the FOXM1 pathway. Our work demonstrates that VT-109 is a promising drug candidate for future clinical studies. Funding for this work is provided by the Congressionally Directed Medical Research Programs through the Peer Reviewed Medical Research Program (PRMRP) under award No. W81XWH-21-1-0639. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.