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

基本信息

  • 批准号:
    10557164
  • 负责人:
  • 金额:
    $ 55.1万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-02-01 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

Acute respiratory distress syndrome (ARDS) is a devastating, proinflammatory disorder resulting from sepsis or severe pneumonia such as SARS-Cov-2. A pathognomonic feature of ARDS is severe tissue injury secondary to a profound release of host cell cytokines. Activation of tumor necrosis factor receptor associated factor (TRAF) and the inflammasome proteins are crucial to inflammation as these proteins link cell surface signals to cytokine release. The mechanistic platform of this proposal resides on our discovery of a relatively new protein, Fbxo3, a ubiquitin E3 ligase subunit, that potently stimulates cytokine secretion from human inflammatory cells by activating TRAFs and inflammasomes. We previously designed and advanced an Fbxo3 inhibitor, BC-1261, to an open IND, however, development was halted as seizures were observed preclinically, limiting dosing in the clinic and thereby minimizing the likelihood of achieving efficacious exposures in humans. Recognizing the opportunity to build upon the achievements of BC-1261, the research strategy outlined in this application is designed with specific milestones to address the critical shortcomings of BC-1261. Here, we propose medicinal chemistry and lead optimization to develop and deliver a potent small- molecule Fbxo3-targeted development candidate with an improved therapeutic index of efficacy to seizure potential (Aim 1). We will also execute pharmacodynamics and pharmacokinetic (PK) studies of lead compounds to nominate a suitable development candidate for IND-enabling studies (Aim 2). Additionally, the candidate will demonstrate dose- dependent oral activity in three translatable ARDS experimental models including a SARS- Cov-2 hamster model with PK properties that support a hospital-based, critical-care therapeutic to inhibit the dysfunctional immune response in acute lung injury patients. Successful completion of this program will bring forth a transformative, first-in-class oral E3 ligase pharmacotherapeutic for critical illness.
急性呼吸窘迫综合征(ARDS)是一种毁灭性的促炎疾病

项目成果

期刊论文数量(0)
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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:
    $ 55.1万
  • 项目类别:
Stabilizing mitochondria in sepsis
稳定败血症中的线粒体
  • 批准号:
    9726032
  • 财政年份:
    2018
  • 资助金额:
    $ 55.1万
  • 项目类别:
Stabilizing mitochondria in sepsis
稳定败血症中的线粒体
  • 批准号:
    10205139
  • 财政年份:
    2018
  • 资助金额:
    $ 55.1万
  • 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:
    $ 55.1万
  • 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:
    $ 55.1万
  • 项目类别:
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
  • 财政年份:
    2014
  • 资助金额:
    $ 55.1万
  • 项目类别:
Immunosuppression in Acute Lung Injury
急性肺损伤中的免疫抑制
  • 批准号:
    10631050
  • 财政年份:
    2014
  • 资助金额:
    $ 55.1万
  • 项目类别:
Immunosuppression in Acute Lung Injury
急性肺损伤中的免疫抑制
  • 批准号:
    10399554
  • 财政年份:
    2014
  • 资助金额:
    $ 55.1万
  • 项目类别:
Admin-Core
管理核心
  • 批准号:
    10204077
  • 财政年份:
    2014
  • 资助金额:
    $ 55.1万
  • 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:
    $ 55.1万
  • 项目类别:

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