Targeting Integrin Signaling in Atherosclerosis

心血管疾病仍然是世界范围内的主要死亡原因。脑缺血最常见的潜在原因 心脏病和中风是动脉粥样硬化。三项开创性研究，Canakinumab抗炎性血栓形成 结果研究(CANTOS)，心血管疾病二级预防的小剂量秋水仙碱(LODOCO2)，以及 秋水仙碱心血管结局试验(Colcot)，已经证明了动脉粥样硬化是一种 炎症性疾病，炎症靶向机制可以减少主要的不良心脏事件 与降脂无关。这里提出的工作代表了一个药物发现和开发计划，旨在 动脉粥样硬化患者的靶向残余炎症风险。它是对融资机会的回应 标题为“催化：小分子和生物制品的产品定义-目标”的公告RFA-HL-23-011 识别和确认，以及初步产品/铅系列识别(R61/R33)。白细胞介素1β(IL-1β) Cantos试验中Canakinumab的靶标。炎症细胞，如活化的单核细胞和巨噬细胞是一种 白介素1β在动脉粥样硬化斑块中的重要来源。它的转录受到严格控制，最大限度地 这种细胞因子在炎性白细胞中的表达需要通过整合素的黏附依赖信号。整合素 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内。 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，这是一种必不可少的 激酶在IL-1β的产生中起重要作用。在以前的工作中，我们确定了β链胞质结构域与Syk的相互作用 这种相互作用的拮抗剂可以阻止整合素介导的单核细胞IL-1β的上调。 在当前的提案中，我们试图通过执行超过1000万的结构引导虚拟屏幕来扩展这项工作 化合物，以确定有效和细胞渗透的药物，可用作药物发现和 发展。我们在该奖项的R61部分的目标是从建模和分子识别化合物 可以在无细胞和基于细胞的整合素分析中验证的动力学模拟：SYK相互作用。一度严苛 “命中”标准已经达到，他们将进入这一奖励机制的R33部分，以评估潜力 小鼠急性炎症模型的毒性、药代动力学和疗效。这里提出的研究将 确定用于药物开发的一系列领先化合物，最终目标是开发一种新的、一流的 药物靶向残余炎症风险的方法。Cantos、LoDoCo2和Colcot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。这个 所提出的方法将针对炎性白细胞中IL-1β调节的上游信号。

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.