Treating Acute Lung Injury via Cytokine Signaling Blockade

 描述（由申请人提供）：急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）由常见的致病过程引起：肺损伤或感染引发压倒性炎症反应（“细胞因子风暴”），导致内皮和上皮通透性增加，炎性细胞、蛋白质和水从血管系统流出到肺泡腔。据估计，ALI的发病率约为79例/100，000人年。对患者的治疗在很大程度上仍然是支持性的，死亡率约为40%。我们已经证明，小GTd 6，Arf 6，是一个汇聚点的信号转导途径的几个炎症介质和细胞因子与证实参与ALI/ARDS。Arf 6激活到其GTP结合状态诱导血管渗漏和水肿，这在ALI/ARDS的病理生理学中起主要作用。因此，我们假设Arf 6的药理学抑制提供了一个机会，以打击多种细胞因子在ALI/ARDS中的作用，这种方法可能比用高度特异性的抑制剂靶向单一途径更有效。在脂多糖（LPS）诱导的ALI的鼠模型中，用我们的Arf 6的小分子抑制剂NAV-2729产生的令人鼓舞的初步体内数据支持该原理。该1期SBIR将通过计算机模拟分子建模工作改进我们目前的NAV-2729系列Arf 6抑制剂，以鉴定具有改善的效力和亲水性的化合物。我们将在生化核苷酸交换试验中确定效价，并在基于机制的细胞Arf 6下拉试验中验证活性。将在体内筛选具有效力和亲水性最佳组合的化合物，以确定药代动力学（PK）参数。然后，我们将证明在小鼠LPS诱导的ALI模型中的概念验证功效。成功完成这些活动将实现两个非常重要的目标。首先，它将提供抑制Arf 6是治疗ALI/ARDS的有前景的新方法的概念验证。其次，它将使我们能够继续在第2阶段的先导优化活动中对Arf 6抑制剂进行药物化学优化（优化效价、选择性、溶解度、ADMET特性、专利性）。该开发项目的成功完成可能会产生一种有效治疗人类ALI/ARDS的疗法。

 DESCRIPTION (provided by applicant): Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) result from a common pathogenic process: pulmonary injury or infection triggers an overwhelming inflammatory response ("cytokine storm") that results in increased endothelial and epithelial permeability and efflux of inflammatory cells, protein, and water from the vascular system into the alveolar space. The incidence of ALI is estimated to be approximately 79 cases per 100,000 person-years. The treatment for those afflicted remains largely supportive with a mortality rate of approximately 40%. We have demonstrated that the small GTPase, Arf6, is a convergence point in the signaling pathways of several inflammatory mediators and cytokines with demonstrated involvement in ALI/ARDS. Activation of Arf6 into its GTP-bound state induces vascular leak and edema, which play major roles in the pathophysiology of ALI/ARDS. Thus, we hypothesize that pharmacological inhibition of Arf6 provides an opportunity to combat actions of multiple cytokines in ALI/ARDS, an approach which may be more effective than targeting single pathways with highly specific inhibitors. This rationale is supported by the encouraging preliminary in vivo data generated with our small molecule inhibitor of Arf6, NAV-2729, in a murine model of lipopolysaccharide (LPS)- induced ALI. This phase 1 SBIR will improve upon our current NAV-2729 series of Arf6 inhibitors through an in silico molecular modeling effort to identify compounds with improved potency and hydrophilicity. We will determine potency in a biochemical nucleotide exchange assay and verify activity in a mechanism-based cellular Arf6 pulldown assay. Compounds with an optimal mix of potency and hydrophilicity will be screened in vivo to determine pharmacokinetic (PK) parameters. We will then demonstrate proof-of-concept efficacy in the murine LPS-induced ALI model. Successful completion of these activities will accomplish two very important goals. First, it will provide proof- of-concept that inhibiting Arf6 is a promising novel approach for treating ALI/ARDS. Second, it will position us to continue medicinal chemistry optimization of Arf6 inhibitors in Lead Optimization activities in phase 2 (optimization of potency, selectivity, solubility, ADMET properties, patentability). Successful completion of this development program may result in a therapy effective for treating humans with ALI/ARDS.