Treating Acute Lung Injury via Cytokine Signaling Blockade

通过细胞因子信号传导阻断治疗急性肺损伤

基本信息

批准号：
8905970
负责人：
ALAN L MUELLER
金额：
$ 22.46万
依托单位：
NAVIGEN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8905970
关键词：
Acute Acute Lung Injury Adult Respiratory Distress Syndrome Albumins Alveolar Animal Model Bacterial Pneumonia Biochemical Biological Assay Biological Availability Biological Warfare Blood Blood Transfusion Blood Vessels Breathing Bronchoalveolar Lavage Fluid Burn injury Cause of Death Cell Count Cells Cellular Assay Chemical Warfare Chemicals Computer Simulation Cytokine Signaling Data Development Dose Drug Kinetics Dyes Edema Epithelial Etiology Evaluation Evans blue stain Extravasation Functional disorder GTP Binding Goals Half-Life Human Incidence Infection Inflammation Mediators Inflammatory Inflammatory Response Pathway Injury Interleukin-6 Intravenous Lead Lipopolysaccharides Lung Measures Mechanical ventilation Modeling Modification Molecular Models Monomeric GTP-Binding Proteins Mus Nucleotides Organ failure Outcome Pathway interactions Patients Permeability Persons Pharmaceutical Chemistry Pharmacology Phase Play Positioning Attribute Preclinical Drug Development Process Program Development Property Proteins Relative (related person)Role Safety Sepsis Sepsis Syndrome Series Signal Pathway Small Business Innovation Research Grant Solubility Structure of parenchyma of lung Supportive care TNF gene Testing Time Toxicology Trauma Treatment Efficacy Vascular System Viral Pneumonia Water Weight base combat compound 30 cytokine design effective therapy hydrophilicity improved in vivo inhibitor/antagonist intraperitoneal lung injury molecular modeling mortality mouse model neutrophil novel strategies pharmacophore public health relevance small molecule

项目摘要

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.

描述（适用提供）：急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是由常见的致病过程造成的：肺损伤或感染触发了压倒性的炎症反应（“细胞因子风暴”），从而导致内皮细胞和上皮性的渗透性和表皮渗透性和膨胀细胞的蛋白质，蛋白质和蛋白质的植物和上皮的空间，从而导致蛋白质和上皮的渗透性，并导致蛋白质和蛋白质。据估计，ALI的发病率为每100,000人年约79例。受折磨者的治疗仍然在很大程度上得到了约40％的死亡率。我们已经证明，小的GTPase ARF6是几种炎症介质和细胞因子的信号传导途径中的收敛点，并且显示出参与ALI/ARDS。 ARF6激活其GTP结合状态会影响血管泄漏和水肿，在ALI/ARDS的病理生理中起着重要作用。这是我们假设对ARF6的药理抑制作用为对抗ALI/ARDS多种细胞因子的作用的机会，这种方法比靶向具有高度特异性抑制剂的单个途径可能更有效。通过我们的小分子抑制剂NAV-2729在脂多糖（LPS）的鼠模型中，由我们的小分子抑制剂（LPS）诱导的Ali产生的小分子抑制剂（LPS）诱导的ALI产生了令人鼓舞的初步体内数据。该阶段1 SBIR将通过在计算机分子建模工作中对当前的NAV-2729系列ARF6抑制剂进行改进，以鉴定具有提高效力和亲水性的化合物。我们将确定生化核交换测定法的效力，并在基于机制的细胞ARF6下拉分析中验证活性。具有最佳效力和亲水性混合物的化合物将在体内筛选，以确定药代动力学（PK）参数。然后，我们将在鼠LPS诱导的ALI模型中证明概念概念的有效性。这些活动的成功完成将实现两个非常重要的目标。首先，它将提供概念证明，即抑制ARF6是治疗ALI/ARDS的概念验证方法。其次，它将在第2阶段（优化效力，选择性，可溶性，ADMET特性，专利性）中继续对ARF6抑制剂进行药物化学优化的药物化学优化。成功完成该开发计划可能会导致有效治疗ALI/ARDS人类的治疗性。