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

项目摘要 钙化性主动脉瓣病(Cavd)是心脏瓣膜最常见的疾病，而且越来越多。 普遍存在于老龄化人群中。这是一种出了名的难以研究和治疗的疾病，并与 在北美，每年大约有15,000人死亡。目前，唯一有效的长期治疗方法是 CAVD是外科或经导管的主动脉瓣置换术；然而，这些置换仅是 推荐给严重的主动脉狭窄患者或接受其他形式的主动脉瓣狭窄手术的患者 心脏病。目前还没有预防性治疗或药物干预来将CAVD作为 这种疾病进展的机制尚不清楚。我们的实验室已经证实了细胞--细胞 黏附蛋白钙粘附素-11(CDH11)在本病中的表达，并表明用一种单抗阻断该蛋白 抗体可预防CAVD的各个方面。虽然这种抗体提供了希望，但它不能在临床上翻译，因为它 将要求无症状的患者每月接受注射，以预防一种可能需要数年时间才能 现在时。因此，需要开发新的药物来预防这种疾病。以前的研究 提示COX2抑制剂塞来昔布与CDH11结合，但与人类主动脉狭窄有关 病人。我们实验室的初步结果表明，非活性类似物二甲基塞来昔布可能是一种 在体外和体内预防CAVD的小分子，因为它也与CDH11结合，但阻止了几个 体外冠脉血管病的特征。此外，还分析了塞来昔布和二甲基醚的结构相似性。 塞来昔布表明磺胺类化合物可能是一类有用的靶向CDH11的小分子。目标是 这项研究的目的是识别与CDH11结合的小分子，这些小分子可以阻止CAVD的进展，并确定 当这些药物在体外使用时，疾病机制会发生变化。我们提出了两个主要的 目的：1)确定二甲基塞来昔布治疗CAVD的体内疗效；2)寻找新的治疗方法 通过利用CDH11结合化合物的高通量、小分子筛选。这项研究将是 第一个展示了小分子在预防CAVD方面的有效性，并将提供对 导致这种疾病的机制。

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.