Abstract
Despite recent therapeutic advances, chronic heart failure (CHF) remains a common and fatal condition. Patients with CHF often have severe symptoms that limit their daily activity and result in a poor quality-of-life. New therapeutic strategies, based on new targets are needed. The signaling pathway consisting of neureguline-1 (NRG1) and its tyrosine kinase receptor ERBB4 could represent such a new target because of its pleiotropic profile and its crucial role in cardiac (patho)physiology. Therapies with recombinant NRG1 are being tested in clinical trials, in which NRG1 is administered intravenously in hospital. This project is based on the premise that small-molecule ERBB4 agonists could be more efficacious in chronic treatment regimens. Therefore, we started a FWO-funded project in 2018 with a high-throughput screening (HTS), resulting in the identification of 8 first-generation ERBB4 agonists that showed ERBB4-specificity and induced antifibrotic effects, but the potency and efficacy compared to NRG1 was relatively low. Recently, in collaboration with the European Lead Factory, we conducted an ultraHTS resulting in 7 structurally unrelated "second-generation" compounds, which are up to a 1000-fold more potent than the first-generation compounds at receptor level. Herein, we propose to study the biological effects of these ERBB4 agonists with the aim to increase our understanding of the cardiac ERBB system and to develop new HF therapies.
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