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Project

Development of ErbB4 Agonists for Treatment of Heart Failure.

Neuregulin-1 (NRG-1) is a natural protein that activates the ErbB4 receptor. The NRG-1/ErbB4 system protects against chronic heart failure, a deadly disease. NRG-1 is currently tested in clinical trials for the treatment of chronic heart failure. Because NRG-1 is a protein, however, it has to be injected intravenously in the hospital, a fact that severely limits applicability of NRG-1 in chronic disorders. A small-molecule with the ability to activate ErbB4 could be an alternative and would allow oral administration. Currently, however, there are no small-molecule activators of ErbB4. Recently, we performed a high-throughput screening to test the ability of 10,000 small-molecules to activate the ErbB4 receptor. Based on this screening, we identified a substructure that could serve as a first scaffold for identification of other activators of ErbB4. We will use this substructure, 3-dimensional shape-based comparisons, and Machine Learning to find other potential ErbB4 activators in a commercial available collection of over 3 million compounds. Compounds will be further evaluated for potency, dose-dependency, solubility, and receptor specificity using different in vitro assays. We will also evaluate pharmacokinetics and in vitro toxicity. The best compounds of the previous steps will be tested in rodent models of heart failure. Success of this project could result in a small-molecule activator of ErbB4, which might lead to novel cures for heart failure.
Date:1 Jan 2020 →  31 Dec 2023
Keywords:HEART FAILURE
Disciplines:Cardiology, Pathophysiology, Drug discovery and development not elsewhere classified, Pharmacotherapy