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：
Rama K Mallampalli
金额：
$ 55.1万
依托单位：
OHIO STATE UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/10557164
关键词：
2019-nCoV Achievement Acute Lung Injury Acute Respiratory Distress Syndrome Address Animal Model Anti-Inflammatory Agents Automobile Driving Biochemical Biological Assay Biological Availability Brain Canis familiaris Carboxylic Acids Cartoons Cause of Death Cell surface Cells Cessation of life Chemistry Clinic Clinical Critical Care Critical Illness Data Development Development Plans Disease Dose Dose Limiting Drug Kinetics Ensure Evaluation Exhibits Experimental Models Foundations Generations Goals Hamsters Hepatocyte Hospitals Human Immune response Industry Standard Inflammasome Inflammation Inflammatory Influenza Injury Interleukin-1 beta Interleukin-6 Lead Link Mediating Metabolism Modeling Multiple Organ Failure Mus Oral Pathway interactions Patients Penetration Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Plasma Pneumonia Property Proteins Rattus Research Secondary to Seizures Sepsis Series Signal Transduction Solubility Structure-Activity Relationship TNF Receptor-Associated Factors TNF gene Testing Therapeutic Therapeutic Index Toxic effect Toxicology Trauma Tumor Necrosis Factor Activation Ubiquitination Virus Inhibitors analog blood-brain barrier penetration cytokine cytokine release syndrome design drug candidate efficacy evaluation efficacy testing improved inhibitor lead optimization link protein lung injury mouse model novel novel strategies pharmacokinetics and pharmacodynamics pre-clinical prevent programs prototype response scale up small molecule success tissue injury ubiquitin-protein ligase

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) 是一种破坏性促炎性疾病由败血症或严重肺炎（例如 SARS-Cov-2）引起。的一个病理特征 ARDS 是继发于宿主细胞细胞因子大量释放的严重组织损伤。激活肿瘤坏死因子受体相关因子（TRAF）和炎性体蛋白是这些蛋白质对炎症至关重要，因为这些蛋白质将细胞表面信号与细胞因子释放联系起来。这该提案的机制平台在于我们发现了一种相对较新的蛋白质， Fbxo3，一种泛素 E3 连接酶亚基，可有效刺激人类细胞因子分泌通过激活 TRAF 和炎症小体来抑制炎症细胞。我们之前设计并将 Fbxo3 抑制剂 BC-1261 推进至开放 IND，但由于临床前观察到癫痫发作，限制临床剂量，从而最大限度地减少在人类中实现有效暴露的可能性。认识到建设的机会根据 BC-1261 的成果，本申请中概述的研究策略是设计具有特定的里程碑，以解决 BC-1261 的关键缺点。在这里，我们提出药物化学和先导化合物优化，以开发和提供有效的小分子 Fbxo3 靶向开发候选分子，治疗指数提高对癫痫发作潜力的功效（目标 1）。我们还将执行药效学和先导化合物的药代动力学 (PK) 研究，以指定合适的开发方案 IND 支持研究的候选人（目标 2）。此外，候选人将证明剂量- 三个可翻译的 ARDS 实验模型（包括 SARS- Cov-2 仓鼠模型具有 PK 特性，支持医院重症监护治疗抑制急性肺损伤患者功能失调的免疫反应。成功的该计划的完成将带来一种变革性的、一流的口服 E3 连接酶危重疾病的药物治疗。