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（由申请人提供）：慢性阻塞性肺病（COPD）是美国第三大死因，但目前尚无可以减缓或预防疾病进展的治疗方法。 COPD 的一个病理特征是生物活性介质（例如基质金属蛋白酶 (MMP) 和炎性体衍生细胞因子 (IL-1 ¿)）的持续作用，产生慢性、持续的气道炎症和损伤，从而导致疾病的病理学。我们最近发现了一种通过蛋白质泛素化实现免疫的新途径，其中一种名为 FBXO3 的促炎蛋白可深刻触发细胞分泌细胞因子（Nature Immunology 14:470-9, 2013）。通过针对 FBXO3，我们开发了一种新型小分子抑制剂。我们的试验数据表明，(i) 我们的主导药物 BC-1261 在香烟烟雾暴露 (CSE) 诱导的 COPD 小鼠模型中减少循环细胞因子、肺泡炎症并预防肺气肿，(ii) FBXO3 抑制剂抑制 CSE 诱导的 MMP 和炎症小体活性，(iii) 与野生型相比，我们进行了目标验证 FBXO3，具有自然发生的保护性、功能低下的 FBXO3 多态性 (FBXO3V221I) 的 COPD 受试者，细胞因子水平降低，肺气肿和疾病进展较轻。因此，我们将 BC-1261 描述为一种用于 COPD 临床前模型（UH2 组件）的新型抗炎化学实体，并证明 BC-1261 在体内使用（UH3 组件）具有最佳的安全性和药品特性。该应用揭示了 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首创化合物。这些研究的执行将成为药物开发计划的基础，该计划将导致炎症治疗的根本性、范式改变的治疗进展，从而导致 IND 申请为 COPD 受试者的新转化计划奠定基础。