Since many years the central concept in our lab at the University of Antwerp, is to discover new targets for treatment of heart failure by exploring the physiology of the heart as an organ showing intercellular cross-talk via diffusible factors and specific receptors. This cross-talk is essential for the heart to develop prenatally, but also to react to stressors throughout life. One of the receptors that has attracted our attention is called ERBB4, since it is expressed by almost each cell within heart, and mediates injury-limiting responses and perhaps even tissue regeneration when activated. Therefore, we hypothesized that small molecules activating the ERBB4 receptor would allow to mimic activation of cellular cross-talk in the heart, and would show a high potential as new therapies.

Identifying small molecules that activate a specific receptor requires testing numerous compounds on a reliable assay. For this project, we used an assay that detects the dimerization of two ERBB4 receptors. At the end of 2017, we hired a brilliant graduate student, Eline Feyen, who began this challenging screening project. Out of more than 10,000 compounds, she identified a series of eight compounds—named EF-1 to EF-8—that induce activation of the ERBB4 receptor in the screening assay. In the following years, many more people got involved and we demonstrated that these compounds acted on the various cardiac cell types as we predicted, and prevented cardiac injury in various mouse models of heart failure. We confirmed that these compounds mainly act through ERBB4, as the effects disappear when the receptor is genetically deleted. Importantly, small molecule-induced ERBB4 activation promotes myocyte cell survival, and counteracts collagen synthesis, direct pharmacological actions not observed with other heart failure treatments. 

In the near future, we aim to attract funding from private investors to continue this exciting project. Our goal is to improve the compounds by modifying their molecular structure to increase their potency and selectivity for the ERBB4 receptor, allowing for lower doses with the same therapeutic effects. We also plan to determine the precise binding site of the compounds on the receptor and assess how quickly the compounds are absorbed and metabolized by the organism. These studies will pave the way for clinical trials.