Identification of small molecule ErbB4 agonist for treatment of heart failure, diabetic kidney injury and fibrotic disorders.

Neuregulin-1 (NRG-1) is the natural agonist of the ErbB4 receptor. Recent evidence clearly shows that the NRG-1/ErbB4 system has protective effects in various chronic disorders including chronic heart failure, chronic diabetic kidney injury, and fibrotic disorders, such as lung fibrosis. All of these are common and deadly disorders. Recombinant Neuregulin-1 is currently tested in phase 3 clinical trials for the treatment of chronic heart failure. However, recombinant NRG-1 has to be injected intravenously in the hospital over the course of 6-8 hours, which is an issue that severely limits applicability of recombinant NRG-1 in chronic disorders. A small molecule that can act as an ErbB4 agonist could circumvent the drawbacks of a recombinant protein and might be more efficacious in treatment of chronic diseases. Currently, there are no small molecule agonists of ErbB4 identified. In this project, we propose a high throughput experiment using a chemical library to identify agonists of the ErbB4 receptor. After in-house optimization of the assay, we will screen a chemical Library consisting of 20.000 compounds at the VIB Compound Screening Facility. Solubility and receptor specificity for ErbB1, ErbB3, and ErbB4 of the hits of this screening assay will be further evaluated using western blotting and ELISA assays. We will test the compound with the highest potency and receptor specificity in validated rodent models of heart failure and fibrosis. We used these animal models before in our laboratory and we successfully showed protective effects of recombinant NRG-1 in all these models. We will also evaluate signs of toxicity in these models without performing a full scale toxicology experiment at this stage. In conclusion, there is robust evidence from our and other laboratories that recombinant NRG-1 has protective effects in various chronic diseases, but the route of administration is prohibitive for wider applicability in the clinic. If this project is successful in identifying a small molecule agonist of ErbB4, we might have the key to novel cures for various chronic diseases.

Keywords:SMALL MOLECULES

Disciplines:Cardiac and vascular medicine, Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences