Small Molecule Therapeutics for Renal Disease

描述（由申请人提供）：进行性肾病仍然是肾病学家面临的一个未解决的挑战，因为它几乎不可避免地导致终末期肾衰竭，这是一种危及生命的疾病，需要进行肾脏替代治疗。很少，如果有的话，目前实行的治疗策略反对分子和细胞程序的细胞凋亡和纤维化，驱动肾脏疾病。分散因子/肝细胞生长因子（SF/HGF）是一种具有抗凋亡和抗纤维化特性的肾营养因子。然而，SF/HGF施用作为基因或蛋白质疗法的临床可行性受到与腺病毒蛋白引起的免疫和炎症反应、蛋白质在溶液中的固有不稳定性、其有限的组织半衰期和过高的成本有关的问题的限制。使用药物发现引擎，包括三维分子建模，噬菌体展示，合理的药物设计，靶向蛋白质组学和体外生物学，Angion Biomedica Corp.已经确定了两个化学上不同的小分子，激活SF/HGF受体c-Met。这些候选药物激活SF/HGF/c-Met信号级联，并在体外发挥细胞保护和抗纤维化作用。在进行性肾病的体内模型中的初步数据表明，这些小分子SF/HGF模拟物对抗间质胶原沉积并保护肾功能。来自监管安全性研究的初步数据表明，这些化学类别成员是安全的，耐受性良好。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库。该I期申请的目标是将体外靶向蛋白质组学与体内生物功效研究相结合，以确定每种化学类别中的主要SF/HGF模拟物，最终目标是将SF/HGF模拟物用于治疗进行性肾病的临床试验。小分子抗纤维化药物在治疗进行性肾病方面具有显著的临床潜力。

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.