PDGFR and KDR Inhibitors for Liver Fibrosis

描述（由申请人提供）：肝纤维化是一种影响全球数千万患者的疾病，是对病毒性乙型或丙型肝炎、过度饮酒、铁超载或肝外梗阻等慢性损伤的肝脏瘢痕反应，可发展为肝硬化、肝功能衰竭和死亡。事实上，由于丙型肝炎流行以及与非酒精性脂肪性肝炎相关的肝脏疾病发病率不断上升，预计未来十年因肝纤维化/肝硬化并发症死亡的人数将增加两倍。目前可用的治疗方法，包括抗病毒药物，在治疗潜在的纤维化方面基本上无效，在大多数情况下，肝移植是唯一有效的治疗方法。肝纤维化，无论其病因如何，反映了共同的细胞和分子病理生理。肝星状细胞的活化和向肌成纤维细胞的转化是纤维形成过程中的主要事件，并且是一个连续的过程，涉及细胞功能的进行性改变。通过血小板衍生生长因子（PDGF）途径和血管内皮生长因子（VEGF）途径的信号在肝纤维化中发挥重要作用。Angion已经鉴定出一种小分子ANG-3154，可以抑制PDGF受体（PDGFR-b）和KDR的激活及其酪氨酸激酶活性。初步数据还表明，该化合物在体内具有抗纤维化作用。我们的长期目标是开发PDGFR-b和KDR的小分子双抑制剂，作为纤维化性肝病和其他器官纤维化疾病的潜在治疗药物。本申请的目的是鉴定这些抑制剂，并在两种临床相关的肝纤维化动物模型中评估它们。

DESCRIPTION (provided by applicant): Liver fibrosis, a disease affecting tens of millions of patients worldwide, is the liver scarring response to chronic injury from viral hepatitis B or C, excessive alcohol use, iron overload or extrahepatic obstructions and can progress to liver cirrhosis, liver failure and death. In fact, deaths from complications of liver fibrosis/cirrhosis are expected to triple over the next decade as a result of the hepatitis C epidemic and the growing incidence of liver disease associated with non-alcoholic steatohepatitis. Currently available therapies, including antivirals, are largely ineffective in treating the underlying fibrosis, and in the majority of cases, liver transplantation is the only effective cure. Liver fibrosis, irrespective of its etiology, reflects common cellular and molecular pathophysiology. Activation of hepatic stellate cells and conversion to myofibroblasts is the dominant event in fibrogenesis, and proceeds along a continuum that involves progressive changes in cellular function. Signaling through the platelet-derived growth factor (PDGF) pathway and vascular endothelial growth factor (VEGF) pathway play important roles in liver fibrosis. Angion has identified a small molecule, ANG-3154, that inhibits activation of the PDGF receptor (PDGFR-b) and the (KDR) and their tyrosine kinase activities. Preliminary data also indicate that this compound is antifibrotic in vivo. Our long-term goal is the development of small molecule dual inhibitors of PDGFR-b and KDR as potential therapeutics for fibrotic liver disease as well as fibrotic disease in other organs. The objective of this application is to identify such inhibitors and evaluate them in two clinically relevant animal models of liver fibrosis. PUBLIC HEALTH RELEVANCE: Small molecule dual inhibitors of the PDGFR and KDR receptors are potential therapeutics for fibrotic disease in the liver, as well as other major organs.