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（由适用提供）：慢性阻塞性肺疾病（COPD）是美国的第三大死亡原因，但目前尚无治疗方法可以减慢或预防疾病进展。 COPD的病原体特征是存在生物活性介质（例如基质金属蛋白酶（MMPS）和炎性源性的细胞因子（IL-1缺））的持续作用，从而产生慢性，无情，气道炎症，从而导致疾病病理生物学的病理学。我们最近通过蛋白质泛素化发现了一种新型免疫学途径，从而促炎蛋白（称为FBXO3）深刻触发细胞的细胞因子分泌（自然免疫学14：470-9，2013）。通过靶向FBXO3，我们开发了一个新型的小分子抑制剂属。我们的试点数据表明（i）我们的铅药物BC-1261降低了循环细胞因子，异形感染，并且可以防止香烟烟雾暴露（CSE）诱导的COPD鼠模型中的肺气肿，（ii）FBXO3抑制剂抑制CSE诱导的MMP和狂热的活动（III），并且与野生型（III）相比，我们已经对此进行了比较。 FBXO3，具有天然受保护的，低功能的FBXO3多态性的COPD受试者（FBXO3V221I）降低了细胞因子水平，较严重的肺气肿和疾病进展。因此，我们将将BC-1261表征为用于COPD临床前模型（UH2组件）的新型抗炎化学实体，并证明BC-1261对体内使用（UH3组件）具有最佳的安全性和药物产品概况。该应用揭示了一个新的分子靶标（FBXO3）基础COPD发病机理，并且是针对COPD泛素蛋白蛋白酶体系统的独特的一流化合物。这些研究的执行将是一项药物开发计划的基础，该计划将导致基本的，改变范式改变的治疗方法，以治疗感染，从而导致IND申请为COPD受试者的新翻译计划奠定了基础。