Identifying activators of interferon regulatory factors for neuroprotection.

摘要 在美国，中风是发病率和死亡率的主要原因。然而，只有不到10%的患者 有资格接受目前批准的组织纤溶酶原激活剂或血栓切除术的干预。我们寻求 开发新的治疗方法以减少缺血引起的损伤和功能障碍的程度 大脑损伤，这是一个重要的未得到满足的医疗需求领域。我们发现干扰素调节因子 (IRF)介导的基因转录可能代表了一种内源性神经保护机制，即 与减少缺血损伤有关。使用中风的细胞和小鼠模型，我们有 证明了在缺血损伤后给予已知的诱导IRF的化合物 介导的基因转录，显著降低了损伤程度。这些结果表明，激活 卒中后IRF转录因子的表达可能是治疗卒中的一种可行的治疗干预措施 病人。这一STTR计划的最终目标是确定在两种情况下诱导IRF转录的化合物 小鼠和人类细胞，但具有最小的非靶标免疫活性。我们将用以下物质来鉴定化合物 可接受的目标规格，通过HIT到Lead方案优化这些化合物，并最终测试 在小鼠脑缺血损伤模型中的疗效。 我们提出以下目标： 目标1：使用一种新的神经保护剂，确定用于治疗开发的先导化合物 经过实验验证的高通量筛选平台。 目的2：通过HIT-TO-铅表征对铅化合物进行评价和排序。 目的3：评估先导化合物的PK和耐受性，并在小鼠模型中确定疗效 脑缺血损伤。

Abstract Stroke is a leading cause of morbidity and mortality in the United States. However less than 10% of patients are eligible for the current approved interventions of tissue plasminogen activator or thrombectomy. We seek to develop new therapeutics to reduce the extent of damage and functional impairment resulting from ischemic injury to the brain, an area of significant unmet medical need. We have found that interferon regulatory factor (IRF) mediated gene transcription may represent an endogenous mechanism of neuroprotection that is associated with a reduction in ischemic injury. Using both cell and mouse models of stroke we have demonstrated that administration of compounds following the ischemic insult, that are known to induce IRF mediated gene transcription, significantly reduces the extent of damage. These results indicate that activation of IRF transcription factors following stroke may be a viable therapeutic intervention for the treatment of stroke patients. The ultimate goal of this STTR program is to identify compounds that induce IRF transcription in both mouse and human cells but with minimal off-target immune activity. We will identify compounds with acceptable target specification, optimize these compounds through hit to lead protocols and ultimately test for efficacy in a mouse model of cerebral ischemic injury. We propose the following aims: Aim 1: Identify lead compounds for therapeutic development of an acute neuroprotectant using an experimentally validated high throughput screening platform. Aim 2: Evaluate and rank lead compounds through hit to lead characterization. Aim 3: Evaluate PK and tolerability of lead compounds and determine efficacy in a mouse model of cerebral ischemic injury.