Targeting cytokine-mediated pathologies for neuroprotection in treatment of AMD

描述(申请人提供)：年龄相关性黄斑变性(AMD)是最具破坏性的眼神经退行性疾病，约占美国和其他发达国家所有失明病例的50%。其最灾难性的新生血管(湿)形式的三个主要病理因素包括高细胞因子血症和视网膜免疫细胞浸润的局部炎症，穿透视网膜的脉络膜血管不受控制的新生血管生长，以及导致光感受器退化的视网膜血管渗漏。所有上述过程都是由促炎症/促血管生成的细胞因子协调的，包括作为主要参与者之一的血管内皮生长因子。玻璃体内注射的标准护理抗血管内皮生长因子生物制剂改善了不到一半患者的视力。血管内皮生长因子与其他细胞因子之间一定程度的功能冗余，以及血管内皮生长因子阻滞剂由于白细胞浸润代偿性升高而导致的抗炎效果差，都是造成这种高水平的关键因素 无应答者的比例。我们提出的新的治疗方法旨在改善治疗反应和药物输送方式。小分子GTP酶Arf6被广泛认为是一种很有前景的药物靶点，它在破坏内皮间黏附连接的稳定性方面发挥着重要作用，在促进细胞因子介导的血管高通透性、血管生成和免疫反应方面发挥着重要作用。与血管内皮生长因子相比，Arf6的相关潜在优势包括：i)它处于与AMD发病相关的多个细胞因子信号通路的汇合点；ii)显示参与了细胞因子介导的血管通透性的控制，但不参与细胞因子的合成，这使得通过直接靶向白细胞渗透来控制炎症成为可能，同时仍然避免了全球免疫抑制；iii)小分子的可药性，这些小分子可能适合非侵入性给药。在HTS中发现了一系列结构一流的小分子Arf6抑制剂，具有低微摩尔效力、机械处理能力、新生SAR、相对于一组其他GTP酶的选择性以及在细胞模型和最重要的两个新生血管性AMD小鼠模型中的有效性。顶级化合物被建议作为药物化学优化的起点，该优化旨在与NIH蓝图神经治疗网络合作开发一种新的视网膜神经保护药物候选药物。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the most devastating ocular neurodegenerative disorder that accounts for approximately 50% of all blindness cases in the United States and other developed nations. Three major pathological factors of its most catastrophic neovascular (wet) form include local inflammation with hypercytokinemia and retinal infiltration with immune cells, uncontrolled neovascular growth of choroidal blood vessels penetrating the retina and retinal vascular leakage that leads to degeneration of photoreceptors. All the above processes are orchestrated by pro-inflammatory/pro-angiogenic cytokines including VEGF as one of the major players. The standard-of-care anti-VEGF biologics delivered intravitreally improve visual acuity in less than half of the patient population. Both certain degree of functional redundancy between VEGF and other cytokines and poor anti-inflammatory efficacy of VEGF-blockers due to compensatory elevations in leukocyte infiltration are among the key factors that apparently account for the high proportion of non-responders. The new therapeutic approach we propose is aimed to improve both therapeutic responsiveness and drug delivery mode. The small GTPase Arf6 has been extensively validated as a promising drug target that, by virtue of its central role in destabilizig interendothelial adherens junctions, is prominently involved in promoting cytokine-mediated vascular hyperpermeability, angiogenesis and immune response. The relevant potential advantages of Arf6 over VEGF include i) its position at a convergence point of multiple cytokine signaling pathways that are associated with AMD pathogenesis; ii) demonstrated involvement in control of cytokine- mediated vascular permeability but not cytokine synthesis that opens a possibility to manage inflammation by directly targeting leukocyte infiltration while still avoidin global immunosuppression; iii) druggability with small molecules that are potentially amenable to non-invasive delivery. A first-in-class structural series of small molecule Arf6 inhibitors with demonstrated low micromolar potency, mechanistic tractability, nascent SAR, selectivity over a panel of other GTPases as well as efficacy in cellular models and, most importantly, in two mouse models of neovascular AMD has been found in HTS. Top compounds are proposed as starting point for the medicinal chemistry optimization that is aimed at development of a novel retinal neuroprotective drug candidate in collaboration with the NIH Blueprint Neurotherapeutics Network.