Small molecule-induced ERBB4 activation to treat heart failure

Abstract Heart failure is a common and deadly disease, requiring new therapeutic approaches. The neuregulin-1 (NRG1)/erythroblastic leukemia viral oncogene homolog 4 (ERBB4) pathway is an interesting target because of its cardioprotective effects. The therapeutic use of recombinant NRG1 has been difficult, because it requires intravenous administration and is non-selective for the ERBB4 receptor. Moreover, development of small-molecule agonists of receptor dimers is generally considered to be challenging. Here, we hypothesized that small-molecule-induced activation of ERBB4 is feasible and can protect against myocardial cell death and fibrosis. To this end, we screened 10,240 compounds for their ability to induce homodimerization of ERBB4. We identified a series of 8 structurally similar compounds (named EF-1 – EF-8) that concentration-dependently induced ERBB4 dimerization, with EF-1 being the most potent. EF-1 decreased in an ERBB4-dependent manner cell death and hypertrophy in cultured atrial cardiomyocytes and collagen production in cultured human cardiac fibroblasts. EF-1 also inhibited angiotensin-II (AngII)-induced myocardial fibrosis in wild-type mice, but not in Erbb4-null mice. Additionally, EF-1 decreased troponin release in wild-type mice treated with doxorubicin (DOX), but not in Erbb4-null mice. Finally, EF-1 improved cardiac function in a mouse model of myocardial infarction (MI). In conclusion, we show that small-molecule-induced ERBB4 activation is possible, displaying anti-fibrotic and cardiomyocyte protective effects in the heart. This study can be the start for the development of small-molecule ERBB4 agonists as a novel class of drugs to treat heart failure.