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Small-molecule-induced ERBB4 activation to treat heart failure
Julie M T Cools1, Bo K Goovaerts1, Eline Feyen1
1Laboratory of PhysioPharmacology, University of Antwerp, Antwerp, Belgium.
Nature Communications
|January 10, 2025
Summary
Small molecules activating ERBB4 show promise for treating heart failure. This approach bypasses limitations of current therapies, offering a potential new drug class for heart protection.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Heart failure is a leading cause of death, necessitating novel therapeutic strategies.
- The neuregulin-1/ERBB4 signaling pathway exhibits cardioprotective effects.
- Current recombinant neuregulin-1 therapies face challenges including intravenous delivery and limited receptor specificity.
Purpose of the Study:
- To investigate the potential of small-molecule ERBB4 activation as a therapeutic approach for heart failure.
- To identify compounds that can activate ERBB4 and assess their efficacy in preclinical models.
Main Methods:
- Screening of 10,240 compounds to identify ERBB4 activators.
- Assessing the effects of identified compounds on cardiomyocyte cell death, hypertrophy, and cardiac fibroblast collagen production.
- Evaluating the efficacy of the lead compound (EF-1) in mouse models of angiotensin-II-induced fibrosis, doxorubicin cardiotoxicity, and myocardial infarction.
Main Results:
- Eight compounds, including EF-1, were identified that induce ERBB4 dimerization.
- EF-1 demonstrated ERBB4-dependent reduction in cardiomyocyte death and hypertrophy, and decreased collagen production in cardiac fibroblasts.
- In vivo, EF-1 mitigated fibrosis and cardiac damage in wild-type mice, with efficacy dependent on ERBB4 expression.
Conclusions:
- Small-molecule activation of ERBB4 is a viable strategy for cardioprotection.
- This approach offers a potential new class of drugs for heart failure treatment, overcoming limitations of existing therapies.
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