Targeting Cadherin-11 for the Treatment of Calcific Aortic Valve Disease

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Project Summary Calcific aortic valve disease (CAVD) is the most common affliction of the cardiac valves and is becoming more prevalent in aging populations. It is a notoriously difficult disease to study and treat, and is responsible for approximately 15,000 deaths per year in North America. Currently, the only effective, long-term treatments for CAVD are surgical or transcatheter aortic valve replacements; however, these replacements are only recommended for patients with severe aortic stenosis or in patients undergoing surgery for another form of heart disease. There is no preventative therapy or pharmacological intervention to treat CAVD as the mechanisms underlying this disease’s progression are poorly understood. Our lab has implicated the cell-cell adhesion protein cadherin-11 (CDH11) in this disease and shown that blocking this protein with a monoclonal antibody prevents every aspect of CAVD. While this antibody provides hope, it is not clinically translatable, as it would require asymptomatic patients to receive monthly injections to prevent a disease that can take years to present. Thus, development of novel pharmaceuticals is needed to prevent this disease. Previous research indicates that the COX2 inhibitor celecoxib binds to CDH11, but is associated with aortic stenosis in human patients. Preliminary results from our lab indicate the inactive analog celecoxib, dimethyl celecoxib, could be a small molecule that prevents CAVD both in vitro and in vivo as it also binds CDH11 but prevents several hallmarks of CAVD in vitro. Additionally, analysis of the structural similarities between celecoxib and dimethyl celecoxib indicate that sulfonamides could be a useful class of small molecules for targeting CDH11. The goal of this study is to identify CDH11-binding small molecules that block the progression of CAVD and determine the disease mechanisms that are altered in vitro when these drugs are administered. We present two primary aims: 1) determine the efficacy of dimethyl celecoxib as a therapeutic for CAVD in vivo and 2) identify novel CDH11 binding compounds through the use of high-throughput, small molecule screening. This study will be the first to demonstrate the effectiveness of small molecules in preventing CAVD and will provide insight into the mechanisms that cause this disease.