Identification of novel small molecule inhibitors of Arf6 for the treatment of va

鉴定用于治疗 va 的新型 Arf6 小分子抑制剂

• 批准号: 8453229
• 负责人: Kirill Ostanin
• 金额: $ 15.06万
• 依托单位: NAVIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8453229
• 关键词: ADP-ribosylation factor 6; Adhesions; Adopted; Affect; Age related macular degeneration; American; Antibodies; Attention; Avastin; Background Diabetic Retinopathy; Biochemical; Biochemical Pathway; Biological; Blindness; Blood Vessels; Cell division; Cell model; Cell physiology; Cells; Cellular Assay; Chemicals; Clinical Paths; Cues; Cytochrome P450; Data; Developed Countries; Development; Diabetic Retinopathy; Diagnosis; Disease; Disease model; Drug Formulations; Drug Kinetics; Edema; Endothelium; Equilibrium; Evaluation; Eye diseases; GTP-Binding Proteins; Goals; Growth Factor; Homeostasis; Immunoglobulin Fragments; In Vitro; Inflammation; Injection of therapeutic agent; Intercellular Junctions; Laboratories; Lead; Legal Blindness; Legal patent; Ligands; Literature; Lucentis; Marketing; Mediating; Medical; Metabolic; Modeling; Monomeric GTP-Binding Proteins; Oral; Oral Administration; Pathogenesis; Pathologic; Pathologic Neovascularization; Pathway interactions; Patients; Permeability; Phase; Positioning Attribute; Publishing; Retinal; Retinal Diseases; Retinal Edemas; Retinal Neovascularization; Role; Route; Safety; Series; Signal Transduction; Small Business Innovation Research Grant; Small Interfering RNA; Solubility; Specificity; Technology; Testing; Therapeutic; Topical application; Tyrosine Kinase Inhibitor; United States; Universities; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vision; Wisconsin; Work; angiogenesis; aptamer; base; bevacizumab; cell motility; cost; cytokine; diabetic; drug development; high throughput screening; improved; in vitro Model; in vivo; inhibitor/antagonist; innovation; interest; macular edema; member; migration; neovascularization; new therapeutic target; novel; preclinical study; public health relevance; ranibizumab; receptor; response; screening; small molecule; trafficking; vascular bed

DESCRIPTION (provided by applicant): Age-Related Macular Degeneration is the most common cause of legal blindness in people over 60, affecting an estimated 1.6 million patients. Additionally, over 400,000 diabetic Americans are diagnosed each year with vision-threatening retinal edema and/or neovascularization. The main therapeutic strategies that have been successful to date have focused on reducing the signals from the destabilizing pathways. This is the basis of anti-VEGF therapies which are costly biologics administered by intraocular injection, typically once monthly. Navigen seeks to explore an alternative and innovative approach to treating the pathologic angiogenesis and endothelial hyperpermeability of the retinal and choroidal vascular beds. Our approach restores the balance toward vascular homeostasis by stimulating vascular stabilization signals. Through its work on guidance cues, the laboratory of Navigen's scientific co-founder, Dr. Dean Li, identified a novel endothelial- specific receptor, Robo4, that when activated by its cognate ligand, Slit2, stabilizes the endothelium and inhibits pathologic cytokine- and growth factor-induced angiogenesis and vascular leak by inhibiting the activation of ADP-ribosylation factor-6 (Arf6). These findings suggest that Robo4 activation, and specifically inhibition of Arf6, provides vascular stabilization signals that actively instruct the endothelium to maintain cell- cell junctions and limit vascular leak and invasion. Our preliminary data and the published literature support the relevance of Arf6 in vascular eye disease. This proposal outlines a strategy to identify novel small molecule inhibitors of Arf6 and to test these in in vitro models of vascular eye disease. By adopting an approach based on identifying small molecule inhibitors of Arf6, we anticipate that potential market advantages include: a small molecule for which topical or oral administration are feasible; a broad based approach to blocking VEGF and other cytokine mediated leak and angiogenesis, and a distinct biochemical pathway that may either replace or augment current anti-VEGF centric therapies.

描述（由申请人提供）：视网膜相关黄斑变性是60岁以上人群中法律的失明的最常见原因，影响约160万患者。此外，每年有超过400，000名糖尿病美国人被诊断患有威胁视力的视网膜水肿和/或新血管形成。迄今为止成功的主要治疗策略集中在减少来自不稳定途径的信号。这是抗VEGF疗法的基础，抗VEGF疗法是通过眼内注射施用的昂贵的生物制剂，通常每月一次。Navigen旨在探索一种替代和创新的方法来治疗视网膜和脉络膜血管床的病理性血管生成和内皮通透性过高。我们的方法通过刺激血管稳定信号来恢复血管稳态的平衡。通过对引导线索的研究，Navigen科学联合创始人Dean Li博士的实验室鉴定了一种新型内皮特异性受体Robo 4，当被其同源配体Slit 2激活时，通过抑制ADP-核糖基化因子-6（Arf 6）的激活来稳定内皮并抑制病理性细胞因子和生长因子诱导的血管生成和血管渗漏。这些发现表明，Robo 4的激活，特别是Arf 6的抑制，提供了血管稳定信号，积极指导血管的稳定。 内皮细胞，以维持细胞-细胞连接并限制血管渗漏和侵袭。我们的初步数据和已发表的文献支持Arf 6在血管性眼病中的相关性。该提案概述了一种策略，以确定新的小分子抑制剂Arf 6和测试这些血管性眼病的体外模型。通过采用基于鉴定Arf 6的小分子抑制剂的方法，我们预计潜在的市场优势包括：局部或口服给药可行的小分子;阻断VEGF和其他细胞因子介导的渗漏和血管生成的广泛基础的方法，以及可以替代或增强当前以抗VEGF为中心的疗法的独特的生化途径。