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）：中风是一个重大的公共卫生问题，美国死亡率比其他涉及心血管系统和癌症的疾病仅次于其他疾病。我们建议通过针对Ca2+稳态的关键调节剂Ca2+/CAM依赖性蛋白激酶II（CAMKII）来追求缺血性中风的神经保护作用。 CAMKII的抑制代表了缺血性中风神经保护症的一种新型范式，基于阻止CaMKII对Ca2+过载的影响，以及其对神经毒性介体的更直接影响。有两个发展为我们提供了缺血性中风中有效的小分子CAMKII抑制剂的基本原理和机会。首先，CAMKII的多动症已被证明可以促进谷氨酸兴奋性毒性的细胞死亡，而激酶的抑制剂是原位和大脑中动脉闭塞（MCAO）模型的神经保护剂。其次，我们借此机会重新启动了CAMKII抑制剂计划最初在药物上进展，现在我们正在基于人类酶的第一个晶体结构的见解来加速。我们的建议相对简单，为了增加我们开发的有效抑制剂的中枢神经系统渗透，并在永久性闭塞MCAO模型中测试了优化的铅化合物。我们设计了许多修饰，以增加化合物的亲脂性，目的是增加其中枢神经系统渗透。这些化合物将在体外分析激酶抑制和选择性，并在神经元培养物中抑制和保护谷氨酸兴奋性。将根据MDR ----- MDCK单层的双向渗透率选择具有最大CNS渗透潜力的抑制剂及其在体内的大脑/血浆分布。将在大鼠永久遮挡MCAO模型中测试铅中枢神经系统穿透抑制剂。我们将使用激酶活性的生物标志物监测体内CAMKII抑制程度，并量化抑制剂对梗死大小的影响。缺血性中风中成功证明----的概念将使我们定位II期SBIR提案，以优化药物的特性，并对铅化合物进行研究。 公共卫生相关性：中风是一个主要的公共卫生问题，美国死亡率率是涉及心血管系统和癌症的其他疾病的第三名。最近的数据暗示Ca2+/CAM-依赖性蛋白激酶II（CAMKII）是Ca2+信号传导的主要介体，在缺血性损伤中。我们旨在增加有效的CAMKII抑制剂的大脑渗透，并在人类缺血性中风的动物模型中测试优化的铅化合物，以确保功效。