Targeting CaM Kinase II for Neuroprotection in Ischemic Stroke

靶向 CaM 激酶 II 对缺血性中风的神经保护

• 批准号: 8251625
• 负责人: Howard Schulman
• 金额: $ 24.97万
• 依托单位: ALLOSTEROS THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8251625
• 关键词: ABCB1 gene; Affinity; Animal Model; Biological Markers; Brain; Calcium/calmodulin-dependent protein kinase; Cardiovascular system; Cell Death; Cells; Data; Development; Disease; Enzymes; Glutamates; Grant; Homeostasis; Human; Hyperactive behavior; In Situ; In Vitro; Infarction; Inhibitory Concentration 50; Ischemia; Ischemic Stroke; Lead; Licensing; Malignant Neoplasms; Mediator of activation protein; Middle Cerebral Artery Occlusion; Modeling; Modification; Monitor; Neurons; Penetration; Peptides; Permeability; Pharmaceutical Preparations; Phase; Phosphotransferases; Plasma; Positioning Attribute; Property; Public Health; Rattus; Signal Transduction; Site; Small Business Innovation Research Grant; Stroke; Structure; Testing; Therapeutic; TimeLine; base; calmodulin-dependent protein kinase II; design; efficacy testing; excitotoxicity; improved; in vivo; inhibitor/antagonist; insight; kinase inhibitor; lipophilicity; monolayer; mortality; neuroprotection; neurotoxicity; novel; pre-clinical; programs; small molecule

DESCRIPTION (provided by applicant): Stroke is a major public health problem, with a US mortality rate that ranks third behind other diseases involving the cardiovascular system and cancer. We propose to pursue neuroprotection in ischemic stroke by targeting a key regulator of Ca2+ homeostasis, Ca2+/CaM-dependent protein kinase II (CaMKII). Inhibition of CaMKII represents a novel paradigm in ischemic stroke-neuroprotection based on blocking the effects of CaMKII on Ca2+ overload as well as its more direct effect on mediators of neurotoxicity. Two developments provide us with the rationale and opportunity to test potent small molecule CaMKII inhibitors in ischemic stroke. First, hyperactivity of CaMKII has been shown to promote cell death in glutamate excitotoxicity while inhibitors of the kinase are neuroprotective in situ and in the middle cerebral artery occlusion (MCAO) model. Second we have taken the opportunity to restart a CaMKII inhibitor program initially advanced at a pharm and which we are now accelerating based on insights from the first crystal structures of the human enzyme. Our proposal is relatively straightforward, to increase CNS penetration of the potent inhibitors we developed and test the optimized lead compound in a permanent occlusion MCAO model. We have designed a number of modifications that increase lipophilicity of our compounds with the aim of increasing their CNS penetration. The compounds will be analyzed for kinase inhibition and selectivity in vitro, and for inhibition and protection from glutamate excitotoxicity in neuronal cultures. The inhibitor with the greatest potential for CNS penetration will be selected based on bidirectional permeability through MDR----MDCK monolayers and its brain/plasma distribution in vivo will be quantified. The lead CNS penetrating inhibitor will be tested in the rat permanent occlusion MCAO model. We will monitor the degree of CaMKII inhibition achieved in vivo using biomarkers of kinase activity and quantify the effect of the inhibitor on infarct size. A successfully proof----of----concept in ischemic stroke will position us for a Phase II SBIR proposal to optimize the drug----like properties and conduct IND enabling studies of the lead compound. PUBLIC HEALTH RELEVANCE: Stroke is a major public health problem with a US mortality rate that ranks third behind other diseases involving the cardiovascular system and cancer. Recent data implicate hyperactivity of Ca2+/CaM- dependent protein kinase II (CaMKII), a major mediator of Ca2+ signaling, in ischemic damage. We aim to increase the brain penetration of our potent CaMKII inhibitors and test the optimized lead compound for efficacy in an animal model of human ischemic stroke.ischemic stroke.

描述（由申请人提供）：中风是一个主要的公共卫生问题，在美国的死亡率排名第三，仅次于其他涉及心血管系统和癌症的疾病。我们建议通过靶向Ca 2+稳态的关键调节因子Ca 2 +/CaM依赖性蛋白激酶II（CaMKII）来寻求缺血性卒中的神经保护。CaMKII的抑制代表了缺血性卒中神经保护的新范例，其基于阻断CaMKII对Ca 2+过载的作用以及其对神经毒性介质的更直接的作用。两项进展为我们提供了在缺血性卒中中测试有效的小分子CaMKII抑制剂的理由和机会。首先，已显示CaMKII的过度活性促进谷氨酸兴奋性毒性中的细胞死亡，而激酶的抑制剂在原位和大脑中动脉闭塞（MCAO）模型中具有神经保护作用。第二，我们利用这个机会重新启动了一个最初在制药公司推进的CaMKII抑制剂项目，我们现在正在加速基于人类酶的第一个晶体结构的见解。我们的建议是相对简单的，以增加中枢神经系统渗透的有效抑制剂，我们开发和测试优化的先导化合物在永久闭塞MCAO模型。我们已经设计了许多修饰，增加我们的化合物的亲脂性，目的是增加其CNS渗透。将分析化合物的体外激酶抑制和选择性，以及神经元培养物中谷氨酸兴奋性毒性的抑制和保护。将根据通过MDR-MDCK单层的双向渗透性选择CNS渗透潜力最大的抑制剂，并对其体内脑/血浆分布进行定量。将在大鼠永久性闭塞MCAO模型中检测主要CNS穿透抑制剂。我们将使用激酶活性的生物标志物监测体内实现的CaMKII抑制的程度，并量化抑制剂对梗死面积的影响。缺血性卒中概念的成功验证将使我们处于II期SBIR提案的位置，以优化药物样特性并进行IND使先导化合物的研究成为可能。 公共卫生关系：中风是一个主要的公共卫生问题，在美国死亡率排名第三，仅次于其他涉及心血管系统和癌症的疾病。最近的数据表明，在缺血性损伤中，Ca 2 +/CaM依赖性蛋白激酶II（CaMKII）（Ca 2+信号传导的主要介质）过度活跃。我们的目标是增加我们有效的CaMKII抑制剂的脑渗透，并在人类缺血性中风的动物模型中测试优化的先导化合物的功效。