Small-molecule-induced ERBB4 activation to treat heart failure.
Summary
A high-throughput screen identified EF-1, a small-molecule ERBB4 activator that reduces cardiomyocyte injury and cardiac fibrosis via ERBB4-dependent mechanisms. EF-1 conferred protection in angiotensin II, doxorubicin, and myocardial infarction models (sex- and context-dependent), establishing feasibility for a new therapeutic class.
Key Findings
- Screening of 10,240 compounds yielded eight ERBB4-activating chemotypes (EF-1–EF-8), with EF-1 most potent for ERBB4 dimerization.
- EF-1 reduced cardiomyocyte death and hypertrophy and decreased fibroblast collagen production in an ERBB4-dependent manner.
- In vivo, EF-1 inhibited angiotensin II–induced cardiac fibrosis (both sexes) and reduced doxorubicin- and MI-induced damage in females; effects were absent in Erbb4-null mice.
Clinical Implications
ERBB4 agonists could emerge as antifibrotic and cardioprotective therapies for heart failure and chemotherapy-induced cardiomyopathy; translational work is needed to define safety, pharmacokinetics, and patient selection.
Why It Matters
Demonstrates, for the first time, drug-like small-molecule activation of ERBB4 with functional cardioprotective effects across models, addressing limitations of recombinant ligand therapy.
Limitations
- Entirely preclinical; human safety, pharmacokinetics, and dose–response remain unknown.
- Sex- and model-dependent efficacy requires mechanistic clarification and broader validation.
Future Directions
Lead optimization for potency/selectivity, ADME/tox profiling, large-animal efficacy, and phase 1 studies; explore combination with standard heart failure therapies and stratification by sex and etiology.
Study Information
- Study Type
- Basic/Mechanistic research
- Research Domain
- Treatment
- Evidence Level
- V - Translational preclinical discovery with in vitro and multiple in vivo models
- Study Design
- OTHER