Targeting Integrin Signaling in Atherosclerosis

靶向动脉粥样硬化中的整合素信号传导

基本信息

批准号：
10669444
负责人：
Ronald J Biediger
金额：
$ 57.21万
依托单位：
TEXAS HEART INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669444
关键词：
Acute Address Adhesions Anti-Inflammatory Agents Arterial Fatty Streak Atherosclerosis Award B-Cell Antigen Receptor Biological Assay Biological Products CCL2 gene Cardiac Cardiovascular Diseases Cardiovascular system Caring Cause of Death Cell surface Cells Cholesterol Clinical Clinical Trials Colchicine Cytoplasmic Tail Development Disclosure Disease Dose Drug Kinetics Event Fc Receptor Funding Opportunities Future Genetic Transcription Goals Grant Heart Diseases Immune response Immune system In Vitro Inflammation Inflammatory Integrin Inhibition Integrin beta Chains Integrins Interleukin-1 beta Lead Legal patent Leukocyte Trafficking Leukocytes Link Lipids Macrophage Mediating Modeling Mus Myocardial Ischemia Outcome Outcome Study Pathway interactions Patients Permeability Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase Phosphotransferases Play Production Program Development Property Protein Tyrosine Kinase Publishing Receptor Signaling Regulation Residual state Risk Role Route SYK gene Safety Secondary Prevention Seminal Signal Transduction Site Source Specificity Stroke Structure Structure-Activity Relationship TNF gene Testing Thrombosis Toxic effect Toxicity Tests United States Up-Regulation Validation Work adhesion receptor analog antagonist arm assay development atherosclerotic plaque rupture atherothrombosis cardiovascular disorder prevention cytokine design drug development drug discovery improved in vivo interest invention lead series literature survey molecular dynamics molecular modeling monocyte mortality mouse model novel novel strategies novel therapeutic intervention novel therapeutics patient population pharmacologic prevent programs response screening small molecule systemic inflammatory response timeline transmission process vascular inflammation virtual

项目摘要

Cardiovascular disease remains the leading cause of death, worldwide. The most common underlying cause of ischemic heart disease and stroke is atherosclerosis. Three seminal studies, the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS), Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease (LoDoCo2), and the Colchicine Cardiovascular Outcomes Trial (COLCOT), have proven the hypothesis that atherosclerosis is an inflammatory disease, and that targeting mechanisms of inflammation can reduce major adverse cardiac events independent of lipid lowering. The work proposed here represents a drug discovery and development program designed to target residual inflammatory risk in patients with atherosclerosis. It is in response to the funding opportunity announcement RFA-HL-23-011 titled “Catalyze: Product Definition for Small Molecules and Biologics - Target Identification and Validation, and Preliminary Product/Lead Series Identification (R61/R33).” Interleukin-1β (IL-1β) was the target of canakinumab in the CANTOS trial. Inflammatory cells like activated monocytes and macrophage are a significant source of interleukin-1β in atherosclerotic plaques. Its transcription is under tight control, and maximum expression of this cytokine in inflammatory leukocytes requires adhesion dependent signaling through integrins. Integrins transmit signals into cells through direct interactions between their cytoplasmic domains and intracellular effectors. Integrin β-chain cytoplasmic domains interact directly with the non-receptor tyrosine kinase Syk, which is an essential kinase in the production of IL-1β. In previous work, we determined that β-chain cytoplasmic domain interactions with Syk were druggable, and an antagonist of this interaction could prevent integrin mediated upregulation of IL-1β in monocytes. In the current proposal we seek to extend this work by performing a structure-guided virtual screen of over 10 million compounds to identify potent and cell-permeable drugs that can be used as starting points in drug discovery and development. Our objective in the R61 component of this award is to identify compounds from modeling and molecular dynamics simulations that can be validated in both cell-free, and cell-based assays of integrin:Syk interactions. Once strict “hit” criteria have been met, they will enter into the R33 component of this award mechanism for assessment of potential toxicities, pharmacokinetics, and efficacy in an acute model of inflammation in mice. The studies proposed here will identify a lead series of compounds for drug development, with the ultimate goal being to develop a novel, first-in-class approach to pharmacologically target residual inflammatory risk. CANTOS, LoDoCo2, and COLCOT demonstrated that targeting IL-1β either directly or indirectly is a viable approach to treat residual inflammatory risk in atherosclerosis. The proposed approach would target upstream signals in the regulation of IL-1β in inflammatory leukocytes.

心血管疾病仍然是世界范围内导致死亡的主要原因。心脏病和中风是动脉粥样硬化的三项开创性研究，即卡那奴单抗抗炎性血栓形成。结果研究 (CANTOS)、低剂量秋水仙碱用于心血管疾病二级预防 (LoDoCo2) 和秋水仙碱心血管结局试验 (COLCOT) 证明了动脉粥样硬化是一种炎症性疾病，并且针对炎症机制可以减少主要的不良心脏事件这里提出的工作代表了一项药物发现和开发计划，旨在独立于降脂。目标是动脉粥样硬化患者的残余炎症风险，这是对资助机会的回应。公告 RFA-HL-23-011，标题为“催化：小分子和生物制品的产品定义 - 目标” 鉴定和验证，以及初步产品/先导物系列鉴定 (R61/R33)。” Canakinumab 在 CANTOS 试验中的目标是激活的单核细胞和巨噬细胞等炎症细胞。动脉粥样硬化斑块中白细胞介素-1β的重要来源，其转录受到严格控制，并且达到最大程度。这种细胞因子在炎症白细胞中的表达需要通过整合素进行粘附依赖性信号传导。通过细胞质结构域和细胞内效应器之间的直接相互作用将信号传递到细胞中。整合素 β 链胞质结构域直接与非受体酪氨酸激酶 Syk 相互作用，这是一种必需的酪氨酸激酶。在之前的工作中，我们确定了 β 链胞质结构域与 Syk 的相互作用。是可药物化的，并且这种相互作用的拮抗剂可以防止单核细胞中整合素介导的 IL-1β 上调。在当前的提案中，我们寻求通过执行超过 1000 万个结构引导的虚拟屏幕来扩展这项工作化合物来识别有效且细胞渗透性药物，可用作药物发现和我们在该奖项 R61 部分的目标是从建模和分子中识别化合物。动力学模拟可以在整合素：Syk 相互作用的无细胞和细胞分析中进行验证。达到“命中”标准后，将进入该奖励机制的R33部分进行潜力评估本文提出的研究将在小鼠急性炎症模型中进行毒性、药代动力学和功效。确定用于药物开发的一系列先导化合物，最终目标是开发一种新颖的、一流的药理学目标 CANTOS、LoDoCo2 和 COLCOT 的方法证明了这一点。直接或间接靶向IL-1β是治疗动脉粥样硬化残余炎症风险的可行方法。所提出的方法将针对炎症白细胞中 IL-1β 调节的上游信号。