TGFb1 Receptor Inhibitors for Liver Fibrosis

描述(申请人提供)：肝纤维化是一种影响全球数千万患者的疾病，是由于乙型或丙型病毒性肝炎、过度饮酒、铁超载或肝外梗阻造成的慢性损伤导致的肝脏疤痕反应，可发展为肝硬化、肝功能衰竭和死亡。事实上，由于丙型肝炎流行和与非酒精性脂肪性肝炎相关的肝病发病率上升，预计未来十年死于肝纤维化/肝硬变并发症的人数将增加两倍。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，都反映了相同的细胞和分子病理生理学。肝星状细胞的激活和向肌成纤维细胞的转化是纤维化形成的主要事件，并沿着涉及细胞功能进行性变化的连续体进行。细胞因子转化生长因子-1在星状细胞活化和纤维化中起中心作用。转化生长因子-1与其受体(Alk5)结合并激活，后者磷酸化并激活包括Smad2在内的信号蛋白，导致纤维化标志物基因如？SMA表达上调。 我们的长期目标是开发转化生长因子？1受体的小分子抑制剂，作为治疗纤维化肝病的潜在药物。这项应用的目的是识别这些抑制物，并在两种临床相关的肝纤维化动物模型中对它们进行评估。转化生长因子？1受体的小分子抑制剂是治疗肝脏和其他主要器官纤维化疾病的潜在药物。

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 the same 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. The cytokine TGF?1 plays a central role in stellate cell activation and fibrosis. TGF?1 binds to and activates its receptor (ALK5), which phosphorylates and activates signaling proteins including Smad2, resulting in expression of upregulation of fibrotic marker genes, such as ?SMA. Our long-term goal is the development of small molecule inhibitors of the TGF?1 receptor as potential therapeutics for fibrotic liver disease. The objective of this application is to identify such inhibitors and evaluate them in two clinically relevant animal models of liver fibrosis. Small molecule inhibitors of the TGF?1 receptor are potential therapeutics for fibrotic disease in the liver, as well as other major organs.