PDGFR and KDR Inhibitors for Liver Fibrosis

PDGFR 和 KDR 肝纤维化抑制剂

• 批准号: 7801858
• 负责人: Bert J. W. M. Oehlen
• 金额: $ 26.98万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-07 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7801858
• 关键词: Affect; Alcohol consumption; Animal Model; Antiviral Agents; Biological; Biological Assay; Biology; Cell physiology; Cells; Cessation of life; Chronic; Cicatrix; Cirrhosis; Clinical Trials; Collaborations; Coupling; Data; Development; Disease; Drug Kinetics; Epidemic; Etiology; Event; Extrahepatic; Fibrosis; Functional disorder; Gene Expression; Goals; Grant; Hepatic Stellate Cell; Hepatitis B; Hepatitis C; Hepatitis C virus; Histology; In Vitro; Incidence; Injury; Iron Overload; Laboratories; Lead; Ligation; Liver; Liver Cirrhosis; Liver Failure; Liver Fibrosis; Liver diseases; Lung; Measures; Modeling; Molecular; Molecular Models; Myofibroblast; Obstruction; Organ; PDGFRB gene; Pathway interactions; Patients; Pharmaceutical Chemistry; Phosphorylation; Phosphotransferases; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Play; Portal Pressure; Principal Investigator; Property; Protein Tyrosine Kinase; Rattus; Research; Role; Screening procedure; Series; Signal Transduction; Small Business Innovation Research Grant; Solubility; Testing; Therapeutic; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; analog; aqueous; base; bile duct; clinically relevant; cytotoxicity; drug discovery; drug synthesis; expectation; experience; fibrogenesis; in vitro Assay; in vivo; in vivo Model; inhibitor/antagonist; liver function; liver transplantation; medical schools; mimetics; molecular modeling; nonalcoholic steatohepatitis; pre-clinical; product development; public health relevance; receptor; response; safety study; small molecule

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.

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，是对病毒性肝炎B或C、过量饮酒、铁超负荷或肝外梗阻引起的慢性损伤的肝脏瘢痕形成反应，可进展为肝硬化、肝功能衰竭和死亡。事实上，由于丙型肝炎的流行和与非酒精性脂肪性肝炎相关的肝病发病率的增加，预计未来十年肝纤维化/肝硬化并发症的死亡人数将增加两倍。目前可用的疗法，包括抗病毒药物，在治疗潜在的纤维化方面基本无效，并且在大多数情况下，肝移植是唯一有效的治愈方法。肝纤维化，不论其病因，反映了共同的细胞和分子病理生理学。肝星状细胞的活化和转化为肌成纤维细胞是纤维化发生的主要事件，并沿着一个连续体进行，涉及细胞功能的进行性变化。血小板源性生长因子（PDGF）和血管内皮生长因子（VEGF）信号通路在肝纤维化中起重要作用。Angion已经鉴定了一种小分子ANG-3154，其抑制PDGF受体（PDGFR-b）和（KDR）的活化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的小分子双重抑制剂，作为纤维化肝病以及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此类抑制剂，并在两种临床相关的肝纤维化动物模型中对其进行评价。 公共卫生关系：PDGFR和KDR受体的小分子双重抑制剂是肝脏以及其他主要器官中纤维化疾病的潜在治疗剂。