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:
- 金额:$ 153.88万
- 依托单位:
- 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:
- 关键词:ADME StudyAdrenal Cortex HormonesAlveolarAnimalsAnti-Inflammatory AgentsAnti-inflammatoryAscaridilBacterial InfectionsBioavailableBiological AssayBiological MarkersBronchodilator AgentsCartoonsCause of DeathCell secretionCellsChemicalsChronicChronic BronchitisChronic Obstructive Airway DiseaseDataDevelopmentDiseaseDisease ProgressionDisease modelDistalDoseDrosophila pros proteinDrug FormulationsDrug KineticsDrug effect disorderDrug or chemical Tissue DistributionF Box DomainFoundationsGenerationsGenetic PolymorphismImmunityImmunologyIn VitroInfectionInflammationInflammation MediatorsInflammatoryInflammatory ResponseInterleukin-1InvestigationKineticsKnock-outLeadMatrix MetalloproteinasesMediator of activation proteinModelingMolecularMolecular TargetMusNatureOrphanPathogenesisPathway interactionsPeptide HydrolasesPharmaceutical PreparationsPharmacodynamicsPharmacologyPlayPre-Clinical ModelProcessProtein FamilyProteinsPulmonary EmphysemaRouteSafetySeveritiesSeverity of illnessSignal TransductionStagingStreamStructureSurfaceSystemTNF Receptor-Associated FactorsTestingTherapeuticTherapeutic AgentsTherapeutic InterventionTherapeutic UsesToxic effectUbiquitinUbiquitinationValidationairway inflammationalveolar destructionantimicrobialbasecigarette smokingcombatcytokinedesigndrug developmentin vivoinhibitor/antagonistinjured airwaylink proteinmeetingsmicrobialmortalitymulticatalytic endopeptidase complexnovelnovel strategiesnovel therapeuticspre-clinicalpreclinical studypreventprogramsprotein degradationresponsescale upscreeningsmall moleculeubiquitin-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(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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Rama K Mallampalli其他文献
Regulation of inflammasomes by ubiquitination
泛素化对炎症小体的调节
- DOI:
10.1038/cmi.2016.15 - 发表时间:
2016-04-11 - 期刊:
- 影响因子:19.800
- 作者:
Joseph S Bednash;Rama K Mallampalli - 通讯作者:
Rama K Mallampalli
Identification of Sex-Specific Differences in Surfactant Synthesis within the CDP-Choline Pathway
- DOI:
10.1203/00006450-199904020-00340 - 发表时间:
1999-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Diann M McCoy;Ronald G Salome;David J Kusner;Shankar S Iyar;Rama K Mallampalli - 通讯作者:
Rama K Mallampalli
Vascular Endothelial Growth Factor (VEGF) Induces Airway Epithelial Cell Proliferation and Surfactant Protein Gene Expression in Human Fetal Lung In Vitro † 242
血管内皮生长因子(VEGF)在体外诱导人胎儿肺气道上皮细胞增殖和表面活性蛋白基因表达†242
- DOI:
10.1203/00006450-199804001-00263 - 发表时间:
1998-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Michael J Acarregui;Kristie Ramirez;Karen R Brown;Rama K Mallampalli - 通讯作者:
Rama K Mallampalli
Rama K Mallampalli的其他文献
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{{ truncateString('Rama K Mallampalli', 18)}}的其他基金
Developing a Novel E3 Ligase based Anti-inflammatory for ARDS
开发基于 E3 连接酶的新型抗 ARDS 抗炎药物
- 批准号:
10366763 - 财政年份:2022
- 资助金额:
$ 153.88万 - 项目类别:
Developing a Novel E3 Ligase based Anti-inflammatory for ARDS
开发基于 E3 连接酶的新型抗 ARDS 抗炎药物
- 批准号:
10557164 - 财政年份:2022
- 资助金额:
$ 153.88万 - 项目类别:
Regulation of Cardiolin Byosynthesis in Epithelial Injury
上皮损伤中心磷脂合成的调节
- 批准号:
8643329 - 财政年份:2014
- 资助金额:
$ 153.88万 - 项目类别:
Cardiolipin as a Novel Mediator of Acute Lung Injury
心磷脂作为急性肺损伤的新型调节剂
- 批准号:
8608045 - 财政年份:2014
- 资助金额:
$ 153.88万 - 项目类别:
A Transcriptional Program Modulating Epithelial Death and Innate Function - Project 1
调节上皮死亡和先天功能的转录程序 - 项目 1
- 批准号:
10204080 - 财政年份:2014
- 资助金额:
$ 153.88万 - 项目类别:














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