ERBB agonist-1 is a ERBB4 agonist with an EC 50 of 10.5 μM. ERBB agonist-1 enhances NRG1-induced ERBB4 homodimerization. ERBB agonist-1 acts as a cell survival promoter, anti-hypertrophic agent, anti-fibrotic agent, and cardioprotective agent. ERBB agonist-1 is applicable to the research of heart failure [1].
In Vivo, ERBB agonist-1 (EF-1) (2 mg/kg/day; s.c.; daily; 1-4 weeks) exhibits anti-fibrotic and cardioprotective activity in angiotensin II-induced myocardial fibrosis in both male and female C57BL/6N mice, reducing fibrotic tissue and fibrosis-related gene expression[1]. ERBB agonist-1 (2 mg/kg/day; s.c.; daily; 28 days) reduces cardiac dilation and interstitial fibrosis in female Balb/cJ mice following myocardial infarction, with no significant effects observed in male mice[1]. ERBB agonist-1 (2 mg/kg/day; s.c.; daily; 1 week) protects against Doxorubicin -induced acute cardiomyocyte injury in female wild-type C57BL/6N mice, with this effect dependent on ERBB4 expression[1].
In Vitro, ERBB agonist-1 (EF-1) (0.0625-32 μM; 6 h, or 1-32 μM; 10 min pre-incubation + 6 h) potently induces ERBB4 homodimerization in U2OS ERBB4/ERBB4 osteosarcoma cells, with an EC50 of 10.5 μM. This compound acts via a non-competitive binding site relative to NRG1, and enhances NRG1-mediated ERBB4 homodimerization at high concentrations[1]. ERBB agonist-1 (0.0625-32 μM; 6 h) weakly induces ERBB2/ERBB4 heterodimerization and ERBB2/ERBB3 and ERBB1/ERBB1 dimerization in U2OS ERBB2/ERBB4 osteosarcoma cells (EC50 > 32 μM)[1]. ERBB agonist-1 (32 μM; 16 h) alters the gene expression of cardiomyocyte-differentiated iAM and HCF, significantly downregulates the TGF-β and MAPK/ERK pathways in HCF, and shares overlapping gene expression changes with NRG1 in both cell types[1]. ERBB agonist-1 (4-32 μM; 10 min pre-incubation + 24 h) reduces TGF-β1-induced COL3A1 mRNA expression in human cardiac fibroblasts (HCFs) in a dose-dependent manner via an ERBB4-dependent mechanism[1]. ERBB agonist-1 (4-32 μM; 10 min pre-incubation + 4 h) reduces H2O2-induced iAMs cell death in a dose-dependent manner via an Erbb4- and PI3K/Akt signaling pathway-dependent mechanism[1]. ERBB agonist-1 (4-32 μM; 1 h pre-incubation + 24 h) attenuates AngII-induced cardiomyocyte hypertrophy in iAMs in a dose-dependent manner via an ERK1/2-dependent mechanism[1].
References:
[1]. Cools JMT, et al. Small-molecule-induced ERBB4 activation to treat heart failure. Nature communications. 2025 Jan 10;16(1):576.
In Vivo, ERBB agonist-1 (EF-1) (2 mg/kg/day; s.c.; daily; 1-4 weeks) exhibits anti-fibrotic and cardioprotective activity in angiotensin II-induced myocardial fibrosis in both male and female C57BL/6N mice, reducing fibrotic tissue and fibrosis-related gene expression[1]. ERBB agonist-1 (2 mg/kg/day; s.c.; daily; 28 days) reduces cardiac dilation and interstitial fibrosis in female Balb/cJ mice following myocardial infarction, with no significant effects observed in male mice[1]. ERBB agonist-1 (2 mg/kg/day; s.c.; daily; 1 week) protects against Doxorubicin -induced acute cardiomyocyte injury in female wild-type C57BL/6N mice, with this effect dependent on ERBB4 expression[1].
In Vitro, ERBB agonist-1 (EF-1) (0.0625-32 μM; 6 h, or 1-32 μM; 10 min pre-incubation + 6 h) potently induces ERBB4 homodimerization in U2OS ERBB4/ERBB4 osteosarcoma cells, with an EC50 of 10.5 μM. This compound acts via a non-competitive binding site relative to NRG1, and enhances NRG1-mediated ERBB4 homodimerization at high concentrations[1]. ERBB agonist-1 (0.0625-32 μM; 6 h) weakly induces ERBB2/ERBB4 heterodimerization and ERBB2/ERBB3 and ERBB1/ERBB1 dimerization in U2OS ERBB2/ERBB4 osteosarcoma cells (EC50 > 32 μM)[1]. ERBB agonist-1 (32 μM; 16 h) alters the gene expression of cardiomyocyte-differentiated iAM and HCF, significantly downregulates the TGF-β and MAPK/ERK pathways in HCF, and shares overlapping gene expression changes with NRG1 in both cell types[1]. ERBB agonist-1 (4-32 μM; 10 min pre-incubation + 24 h) reduces TGF-β1-induced COL3A1 mRNA expression in human cardiac fibroblasts (HCFs) in a dose-dependent manner via an ERBB4-dependent mechanism[1]. ERBB agonist-1 (4-32 μM; 10 min pre-incubation + 4 h) reduces H2O2-induced iAMs cell death in a dose-dependent manner via an Erbb4- and PI3K/Akt signaling pathway-dependent mechanism[1]. ERBB agonist-1 (4-32 μM; 1 h pre-incubation + 24 h) attenuates AngII-induced cardiomyocyte hypertrophy in iAMs in a dose-dependent manner via an ERK1/2-dependent mechanism[1].
References:
[1]. Cools JMT, et al. Small-molecule-induced ERBB4 activation to treat heart failure. Nature communications. 2025 Jan 10;16(1):576.