Targeting cytokine-mediated pathologies for neuroprotection in treatment of AMD

描述（由申请人提供）：年龄相关性黄斑变性（AMD）是最具破坏性的眼部神经退行性疾病，约占美国和其他发达国家所有失明病例的50%。其最具灾难性的新血管（湿）形式的三个主要病理因素包括局部炎症伴高细胞素血症和免疫细胞浸润视网膜，脉络膜血管不受控制的新血管生长穿透视网膜和视网膜血管渗漏导致光感受器变性。所有这些过程都是由促炎/促血管生成细胞因子策划的，其中VEGF是主要参与者之一。标准治疗的抗vegf生物制剂在不到一半的患者体内确实改善了视力。VEGF与其他细胞因子之间存在一定程度的功能冗余，以及白细胞浸润代偿性升高导致VEGF阻滞剂的抗炎效果较差，这两个因素显然都是导致这种高水平的关键因素

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.