Small-molecule-induced ERBB4 activation to treat heart failure

  • Nat Commun. 2025 Jan 10;16(1):576. doi: 10.1038/s41467-024-54908-5.
Julie M T Cools  #  1 ,  Bo K Goovaerts  #  1 ,  Eline Feyen  #  1 ,  Siel Van den Bogaert  1 ,  Yile Fu  2 ,  Céline Civati  1 ,  Jens Van Fraeyenhove  1 ,  Michiel R L Tubeeckx  1 ,  Jasper Ott  3 ,  Long Nguyen  4  5 ,  Eike M Wülfers  6  7 ,  Benji Van Berlo  1 ,  Antoine A F De Vries  8 ,  Nele Vandersickel  6 ,  Daniël A Pijnappels  8 ,  Dominique Audenaert  4  5 ,  H Llewelyn Roderick  2 ,  Hans De Winter  9 ,  Gilles W De Keulenaer  1  10 ,  Vincent F M Segers  11  12
Affiliations
  • 1. Laboratory of PhysioPharmacology, University of Antwerp, Antwerp, Belgium.
  • 2. Laboratory of Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.
  • 3. Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium.
  • 4. Screening Core, VIB, Ghent, Belgium.
  • 5. Centre for Bioassay Development and Screening (C-BIOS), Ghent University, Ghent, Belgium.
  • 6. Department of Physics and Astronomy, Ghent University, Ghent, Belgium.
  • 7. Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg - Bad Krozingen, Freiburg im Breisbau, Germany and Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
  • 8. Laboratory of Experimental Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
  • 9. Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.
  • 10. Department of Cardiology, ZNA Hospital, Antwerp, Belgium.
  • 11. Laboratory of PhysioPharmacology, University of Antwerp, Antwerp, Belgium. [email protected].
  • 12. Department of Cardiology, University Hospital Antwerp, Antwerp, Belgium. [email protected].
  • # Contributed equally.
PMID: 39794341 DOI: 10.1038/s41467-024-54908-5
Abstract

Heart failure is a common and deadly disease requiring new treatments. The neuregulin-1/ERBB4 pathway offers cardioprotective benefits, but using recombinant neuregulin-1 as therapy has limitations due to the need for intravenous delivery and lack of receptor specificity. We hypothesize that small-molecule activation of ERBB4 could protect against heart damage and fibrosis. To test this, we conduct a screening of 10,240 compounds and identify eight structurally similar ones (EF-1 to EF-8) that induce ERBB4 dimerization, with EF-1 being the most effective. EF-1 reduces cell death and hypertrophy in cardiomyocytes and decreases Collagen production in cardiac fibroblasts in an ERBB4-dependent manner. In wild-type mice, EF-1 inhibits angiotensin-II-induced fibrosis in males and females and reduces heart damage caused by doxorubicin and myocardial infarction in females, but not in Erbb4-null mice. This study shows that small-molecule ERBB4 activation is feasible and may lead to a novel class of drugs for treating heart failure.

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