Small Molecule Therapeutics for Renal Disease

描述(申请人提供)：进行性肾脏疾病仍然是肾科医生尚未解决的挑战，因为它几乎不可避免地导致终末期肾功能衰竭，这是一种危及生命的情况，需要肾脏替代治疗。目前实践中的治疗策略中，很少有人反对导致肾脏疾病的分子和细胞程序的细胞凋亡和纤维化。散射因子/肝细胞生长因子(SF/HGF)是一种具有抗细胞凋亡和抗纤维化作用的肾营养因子。然而，SF/HGF作为基因或蛋白质治疗的临床可行性受到与腺病毒蛋白引起的免疫和炎症反应有关的问题的限制，蛋白质在溶液中的固有不稳定性，其有限的组织半衰期和高昂的成本。Angion Biomedica Corp.利用包括三维分子建模、噬菌体展示、合理药物设计、靶向蛋白质组学和体外生物学在内的药物发现引擎，确定了两个化学上不同的小分子，它们激活了SF/HGF受体c-Met。这些候选药物激活了SF/HGF/c-Met信号通路，并在体外发挥了细胞保护和抗纤维化作用。进展性肾脏疾病体内模型的初步数据表明，这些小分子SF/HGF模拟物可以对抗间质胶原沉积，保护肾功能。来自监管安全研究的初步数据表明，这些化学类成员是安全的，耐受性很好。使用基于合理药物设计的化学取代，我们现在已经围绕这些小分子构建了结构文库。这一第一阶段应用的目标是将体外靶向蛋白质组学与体内生物功效研究结合起来，以便在每一类化学物质中确定一种主要的SF/HGF模拟物，最终目标是将SF/HGF模拟物带入治疗进展性肾脏疾病的临床试验。一种小分子抗纤维化药物在治疗进展性肾脏疾病方面具有重要的临床潜力。

DESCRIPTION (provided by applicant): Progressive renal disease remains an unsolved challenge for the nephrologist, as it almost inevitably leads to end-stage renal failure, a life-threatening condition that necessitates renal replacement therapy. Few, if any, of the currently practiced therapeutic strategies oppose the molecular and cellular programs of apoptosis and fibrosis that drive renal disease. Scatter factor/hepatocyte growth factor (SF/HGF), is a renotrophic factor with anti-apoptotic and anti-fibrotic properties. However clinical feasibility of SF/HGF administration as gene or protein therapy is limited by issues relating to the immune and inflammatory responses evoked by adenoviral proteins, inherent instability of proteins in solution, their limited tissue half-life and exorbitant costs. Using a drug-discovery engine comprising 3-dimensional molecular modeling, phage display, rational drug design, targeted proteomics and in vitro biology, Angion Biomedica Corp. has identified two, chemically distinct, small molecules that activate the SF/HGF receptor c-Met. These drug candidates activate the SF/HGF/c-Met signaling cascade, and exert cytoprotective and anti-fibrotic effects in vitro. Preliminary data in an in vivo model of progressive renal disease indicate that these small molecule SF/HGF mimetics oppose interstitial collagen deposition and preserve renal function. Preliminary data from regulatory safety studies suggest that these chemical class members are safe and well-tolerated. Using rational drug-design based chemical substitutions, we have now constructed structural libraries around these small molecules. The goal of this Phase I application is to couple in vitro targeted proteomics to in vivo bioefficacy studies in order to identify a lead SF/HGF mimetic within each chemical class, with the eventual goal of bringing an SF/HGF mimetic to clinical trials for the treatment of progressive renal disease. A small molecule anti-fibrotic has significant clinical potential for the treatment of progressive renal disease.