Targeting cytokine-mediated pathologies for neuroprotection in treatment of AMD

描述（由申请人提供）：视网膜相关性黄斑变性（AMD）是最具破坏性的眼部神经退行性疾病，占美国和其他发达国家所有失明病例的约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具有高细胞因子血症的局部炎症和免疫细胞的视网膜浸润、穿透视网膜的脉络膜血管的不受控制的新生血管生长和导致光感受器变性的视网膜血管渗漏。所有上述过程都是由促炎/促血管生成细胞因子（包括VEGF作为主要参与者之一）协调的。玻璃体内递送的标准治疗抗VEGF生物制剂在不到一半的患者人群中改善了视力。VEGF和其他细胞因子之间一定程度的功能冗余以及由于白细胞浸润的代偿性升高而导致的VEGF阻断剂的抗炎功效差是明显导致高炎症反应的关键因素。 无应答者的比例。我们提出的新治疗方法旨在改善治疗反应性和药物递送模式。小的GTd 6 Arf 6已被广泛验证为一个有前途的药物靶标，由于其在使内皮间粘附连接不稳定中的中心作用，其显著参与促进精氨酸介导的血管通透性过高、血管生成和免疫应答。Arf 6相对于VEGF的相关潜在优势包括i）其位于与AMD发病机制相关的多种细胞因子信号传导途径的汇聚点; ii）证实参与控制细胞因子介导的血管通透性，但不参与细胞因子合成，这开启了通过直接靶向白细胞浸润来控制炎症同时仍避免整体免疫抑制的可能性; iii）用可能适合于非侵入性递送的小分子的可药用性。在HTS中发现了一类结构系列的小分子Arf 6抑制剂，其具有低微摩尔效力、机械易处理性、新生SAR、对一组其他GTP酶的选择性以及在细胞模型中的功效，最重要的是，在两种新生血管性AMD小鼠模型中的功效。顶级化合物被提议作为药物化学优化的起点，其目的是与NIH蓝图神经治疗网络合作开发一种新型视网膜神经保护药物候选物。

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.