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

基本信息

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
项目类别：
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

项目摘要

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 的一个显着特征是存在持续作用。产生慢性、持续性气道炎症和损伤的生物活性介质（例如基质金属蛋白酶 (MMP) 和炎性体衍生细胞因子 (IL-1 ¿)）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，从而一种称为 FBXO3 的促炎蛋白可深刻触发细胞的细胞因子分泌（Nature Immunology 14:470-9, 2013）。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 可以减少循环细胞因子，肺泡炎症，并在香烟烟雾暴露 (CSE) 诱导的 COPD 小鼠模型中预防肺气肿，(ii) FBXO3 抑制剂抑制 CSE 诱导的 MMP 和炎症小体活性，并且 (iii) 与野生型 FBXO3 相比，我们进行了目标验证，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，肺气肿不那么严重，并且因此，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 在体内使用中具有最佳的安全性和药品特性（UH3）。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。