Ca2+/CaM-Dependent Protein Kinase II: A Novel Target in Heart Failure

Ca2 /CaM 依赖性蛋白激酶 II：心力衰竭的新靶点

基本信息

批准号：
8122706
负责人：
Howard Schulman
金额：
$ 21.29万
依托单位：
ALLOSTEROS THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-15 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8122706
关键词：
Active Sites Animal Model Apoptosis Binding Biochemical Calcium Calcium/calmodulin-dependent protein kinase Cardiac Cardiac Myocytes Cardiac Output Cardiovascular Physiology Catalytic Domain Chemicals Clinical Docking Ensure Event Functional disorder Genetic Goals Heart Diseases Heart failure Homeostasis Hypertrophy In Situ In Vitro Inhibitory Concentration 50 Ion Channel Knock-out Lead Metabolic Molecular Models Mus Neonatal Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phosphorylation Phosphotransferases Positioning Attribute Property Protein Isoforms Protein Kinase Inhibitors Reagent Research Scientist Signal Transduction Solubility Staging Structure Sudden Death Syndrome Synthesis Chemistry Testing TimeLine analog base calmodulin-dependent protein kinase II design efficacy testing improved in vitro Assay inhibitor/antagonist insight lifetime risk meetings molecular modeling novel pre-clinical protein kinase inhibitor prototype sensor small molecule

项目摘要

DESCRIPTION (provided by applicant): Heart disease converts to the clinical syndrome of heart failure when the cardiac output is inadequate to meet metabolic requirements. Evidence now supports that pharmacological targeting of Ca2???? dependent protein kinase II (CaMKII), a sensor of dysregulated calcium homeostasis, will inhibit conversion of early stages of cellular pathophysiology to symptomatic heart failure and sudden death. Inhibition of the kinase with research inhibitors, or by genetic knock-out of the major cardiac isoform, blocks this chain of events in animal models. We propose a strategy to modify a small molecule inhibitor of CaMKII to increase its potency and selectivity, test it biochemically to ensure it has the desired mechanism of action, then test for inhibition of characterized markers of hypertrophy and for apoptosis in neonatal mouse cardiomyocytes. We start with an allosteric CaMKII inhibitor used to demonstrate its cardiovascular functions but has never been pharmacologically optimized and thus have low potency. Guided by our analysis of new crystal structures and structural insights we have developed from docking inhibitors to its active site we have designed a set of compounds that target a unique feature of the allosteric pocket in the active site of CaMKII. Our overall goals for Phase I are to retain and improve the selectivity of the inhibitor while markedly increasing its potency, and to test the lead inhibitor compounds for efficacy then test for inhibition of characterized markers of hypertrophy and for apoptosis it in neonatal mouse cardiomyocytes PUBLIC HEALTH RELEVANCE: Heart failure is a global burden, with the lifetime risk in the developed world above 20% and a consuming focus for patients, clinicians, scientists, and policymakers. Heart disease converts to the clinical syndrome of heart failure when the cardiac output is inadequate to meet metabolic requirements. Evidence now supports that pharmacological targeting of intracellular signaling, in particular of Ca2???? dependent protein kinase II, a sensor of dysregulated calcium homeostasis will inhibit conversion to symptomatic heart failure and sudden death. We propose a strategy to modify a small molecule inhibitor of this protein kinase in ways that increase its potency, analyze it biochemically to ensure it has the desired mechanism of action, then test for inhibition of characterized markers of hypertrophy and for apoptosis it in neonatal mouse cardiomyocytes.

描述（由申请人提供）：心脏病转换为心力衰竭临床综合征，当心脏输出不足以满足代谢需求。现在的证据支持CA2的药理学靶向？？？？依赖性蛋白激酶II（CAMKII）是钙稳态失调的传感器，将抑制细胞病理生理学的早期阶段转化为症状性心力衰竭和猝死。通过研究抑制剂或通过主要心脏同工型的遗传敲除对激酶的抑制作用，阻止了动物模型中的这一事件。我们提出了一种修改CAMKII分子抑制剂以提高其效力和选择性的策略，以生化测试，以确保其具有所需的作用机理，然后测试抑制特征性肥大的特征标记和新生儿小鼠心肌细胞中的凋亡。我们从用于证明其心血管功能的变构CAMKII抑制剂开始，但从未在药理学上优化，因此具有较低的效力。在我们对我们从对接抑制剂到其活跃部位的新晶体结构和结构见解的分析的指导下，我们设计了一套化合物，这些化合物针对Camkii活跃部位的变构袋的独特特征。第一阶段的总体目标是保留和提高抑制剂的选择性，同时显着提高其效力，并测试铅抑制剂化合物的功效，然后测试抑制特征性肥大的特征标记，并在新生儿小鼠中凋亡IT 公共卫生相关性：心力衰竭是全球负担，在20％以上的发达国家中的终生风险是患者，临床医生，科学家和政策制定者的消费重点。当心脏输出不足以满足代谢需求时，心脏病会转化为心力衰竭的临床综合征。现在的证据支持了细胞内信号传导的药理靶向，特别是CA2 ？？？？依赖性蛋白激酶II，钙稳态失调的传感器将抑制转化为有症状的心力衰竭和猝死。我们提出了一种策略，以增加该蛋白激酶的小分子抑制剂的方式，以提高其效力，对生化进行分析，以确保其具有所需的作用机理，然后测试抑制特征性肥大的特征标记和在新生儿小鼠心肌细胞中的凋亡。