Heart failure (HF) affects 700,000 individuals yearly in the United States, accounting for $10-40 billion annual cost. Although the last ten years have seen dramatic improvements in therapeutic approaches to HF, the expanding number of patients with chronic HF and its persistently poor prognosis make it clear that additional novel treatment approaches are necessary. Recent research has identified myocyte enhancer factor 2 (MEF2) as a potentially important mediator of cardiac hypertrophy and subsequent myocardial failure. Myogen will develop high throughput screening assays and will screen for compounds that inhibit MEF2 signaling. In Phase I Myogen will identify the most appropriate high throughput (HT) screening assays in terms of assay stability, ease of preparation and use, reproducibility, and general robustness. In Phase II Myogen will apply selected assays from Phase I for screening compound libraries and peptide and/or nucleic acid aptamer expression libraries to identify inhibitors of MEF2 dependent gene activation. In Phase III Myogen will pursue validation experiments of identified inhibitors of MEF2 signaling, evaluating their ability to block the development of cardiac hypertrophy and heart failure in a variety of animal models. Following validation, Myogen will pursue commercialization by advancing drug candidates into lead optimization and human clinical testing. PROPOSED COMMERCIAL APPLICATIONS: The goal of this project is to develop MEF2 signaling inhibitors. Technology will be developed to identify novel compounds to validate MEF2 as a target for HF drug development and to ultimately develop novel HF therapeutics. Validated targets should prove to be extremely useful in developing therapeutics that halt or reverse the progression of heart muscle disease. It is estimated that for each validated target, approximately $30-40 million in precommercial payments will be generated from licensing fees, R&D funding, milestone payment, and equity. This figure does not include future royalties from commercialization.