2. Academic Validation
  3. Small-molecule-induced ERBB4 activation to treat heart failure

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

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. vincent.segers@uantwerpen.be.
  • 12 Department of Cardiology, University Hospital Antwerp, Antwerp, Belgium. vincent.segers@uantwerpen.be.
  • # 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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