Small-molecule-induced ERBB4 activation to treat heart failure
Julie Cools, Bo Goovaerts, Eline Feyen, Siel Van den Bogaert, Yile Fu, Céline Civati, Jens Van fraeyenhove, Michiel Tubeeckx, Jasper Ott, Long Nguyen, Eike M. Wülfers, B Van Berlo, Antoine A.F. de Vries, Nele Vandersickel, Daniël A. Pijnappels, Dominique Audenaert, H. Llewelyn Roderick, Hans De Winter, Gilles W. De Keulenaer, Vincent F. M. Segers
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.