A New Genus of Ubiquitin-Based Anti-inflammatories for COPD

一类新的基于泛素的慢性阻塞性肺病抗炎药

• 批准号: 8751858
• 负责人: Rama K Mallampalli
• 金额: $ 153.88万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8751858
• 关键词: ADME Study; Adrenal Cortex Hormones; Alveolar; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Ascaridil; Bacterial Infections; Bioavailable; Biological Assay; Biological Markers; Bronchodilator Agents; Cartoons; Cause of Death; Cell secretion; Cells; Chemicals; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Data; Development; Disease; Disease Progression; Disease model; Distal; Dose; Drosophila pros protein; Drug Formulations; Drug Kinetics; Drug effect disorder; Drug or chemical Tissue Distribution; F Box Domain; Foundations; Generations; Genetic Polymorphism; Immunity; Immunology; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-1; Investigation; Kinetics; Knock-out; Lead; Matrix Metalloproteinases; Mediator of activation protein; Modeling; Molecular; Molecular Target; Mus; Nature; Orphan; Pathogenesis; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Play; Pre-Clinical Model; Process; Protein Family; Proteins; Pulmonary Emphysema; Route; Safety; Severities; Severity of illness; Signal Transduction; Staging; Stream; Structure; Surface; System; TNF Receptor-Associated Factors; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Therapeutic Uses; Toxic effect; Ubiquitin; Ubiquitination; Validation; airway inflammation; alveolar destruction; antimicrobial; base; cigarette smoking; combat; cytokine; design; drug development; in vivo; inhibitor/antagonist; injured airway; link protein; meetings; microbial; mortality; multicatalytic endopeptidase complex; novel; novel strategies; novel therapeutics; pre-clinical; preclinical study; prevent; programs; protein degradation; response; scale up; screening; small molecule; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the US, yet currently there exist no treatments that can slow or prevent disease progression. A pathognomonic feature of COPD is the presence of sustained actions of bioactive mediators (e.g. matrix metalloproteinase (MMPs), and inflammasome-derived cytokines (IL-1 ¿)) that produce chronic, unrelenting, airway inflammation and injury thereby contributing to the pathobiology of disease. We recently discovered a novel pathway for immunity through protein ubiquitination whereby a pro-inflammatory protein, called FBXO3 profoundly triggers cytokine secretion from cells (Nature Immunology 14:470-9, 2013). By targeting FBXO3, we developed a novel genus of small molecule inhibitors. Our pilot data indicate that (i) our lead drug, BC-1261, reduces circulating cytokines, alveolar inflammation, and prevents emphysema in a cigarette smoke exposure (CSE)-induced COPD murine model, (ii) that FBXO3 inhibitors inhibit CSE induced MMP and inflammasome activity, and that (iii) we have target validation where compared to wild-type FBXO3, COPD subjects with a naturally occurring protective, hypofunctional FBXO3 polymorphism (FBXO3V221I) have reduced cytokine levels, less severe emphysema, and disease progression. Hence, we will characterize BC-1261 as a new anti-inflammatory chemical entity for use in COPD preclinical models (UH2 Component), and demonstrate that BC-1261 exerts an optimal safety and drug product profile for in vivo use (UH3 Component). This application unveils a new molecular target (FBXO3) underlying COPD pathogenesis and a unique first-in-class compound targeting the ubiquitin-proteasome system for COPD. Execution of these studies will be the basis of a drug development program that will lead to a fundamental, paradigm-changing therapeutic advance for treatment of inflammation leading to an IND application setting the stage for a new translational initiative in COPD subjects.

描述(申请人提供)：慢性阻塞性肺疾病(COPD)是美国第三大死亡原因，但目前还没有可以减缓或防止疾病进展的治疗方法。COPD的一个病因学特征是存在生物活性介质(如基质金属蛋白酶(MMPs)和炎症体衍生细胞因子(IL-1))的持续作用，它们会产生持续的、持续的呼吸道炎症和损伤，从而促进疾病的病理生物学。我们最近发现了一种通过蛋白质泛素化进行免疫的新途径，通过这种途径，一种名为Fbxo3的促炎蛋白可以深刻地触发细胞分泌细胞因子(自然免疫学14：470-9,2013)。通过靶向Fbxo3，我们开发了一类新的小分子抑制剂。我们的试点数据表明：(I)我们的先导药物BC-1261可以减少香烟烟雾暴露(CSE)诱导的COPD小鼠模型中的循环细胞因子、肺泡炎和预防肺气肿；(Ii)Fbxo3抑制剂抑制CSE诱导的基质金属蛋白酶和炎症肌体活性；(Iii)与野生型Fbxo3相比，具有天然保护性、功能低下的Fbxo3基因多态性(FBXO3V221I)的COPD患者细胞因子水平降低，严重程度减轻，疾病进展也得到靶向验证。因此，我们将BC-1261描述为用于COPD临床前模型的新型抗炎化学实体(UH2成分)，并证明BC-1261具有最佳的安全性和体内使用的药物产品概况(UH3成分)。这项应用揭示了COPD发病机制的新分子靶点(Fbxo3)和针对COPD泛素-蛋白酶体系统的独特的一流化合物。这些研究的执行将是药物开发计划的基础，该计划将导致治疗炎症的根本性、改变范式的治疗进展，从而导致IND应用，为COPD受试者的新翻译计划奠定基础。