Developing Ca2+/CaM Kinase II Inhibitors to Treat Arrhythmias in Heart Failure

开发 Ca2/CaM 激酶 II 抑制剂来治疗心力衰竭引起的心律失常

基本信息

批准号：
8393257
负责人：
Howard Schulman
金额：
$ 25.74万
依托单位：
ALLOSTEROS THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8393257
关键词：
Active Sites American Animal Model Arrhythmia Ca(2+)-Calmodulin Dependent Protein Kinase Calcineurin Calcium Calcium/calmodulin-dependent protein kinase Cardiac Cardiac Myocytes Cardiovascular system Cells Chemicals Complex Development Docking Ensure Etiology Evaluation Genetic Goals Government Heart failure Homeostasis Human Hyperactive behavior In Situ In Vitro Inhibitory Concentration 50 Lead Mediator of activation protein Modeling Molecular Models Mus Myocardial Infarction Myocardium Pathway interactions Patients Permeability Persons Pharmaceutical Preparations Phase Phosphotransferases Positioning Attribute Property Protein Kinase Public Health Research Resolution Signal Transduction Structure Structure-Activity Relationship Testing TimeLine Ventricular Arrhythmia base calmodulin-dependent protein kinase II design efficacy testing high risk improved in vivo in vivo Model inhibitor/antagonist insight killings molecular modeling mouse model new therapeutic target novel pre-clinical programs response sensor small molecule sudden cardiac death

Active Sites American Animal Model Arrhythmia Ca(2+)-Calmodulin Dependent Protein Kinase Calcineurin Calcium Calcium/calmodulin-dependent protein kinase Cardiac Cardiac Myocytes Cardiovascular system Cells Chemicals Complex Development Docking Ensure Etiology Evaluation Genetic Goals Government Heart failure Homeostasis Human Hyperactive behavior In Situ In Vitro Inhibitory Concentration 50 Lead Mediator of activation protein Modeling Molecular Models Mus Myocardial Infarction Myocardium Pathway interactions Patients Permeability Persons Pharmaceutical Preparations Phase Phosphotransferases Positioning Attribute Property Protein Kinase Public Health Research Resolution Signal Transduction Structure Structure-Activity Relationship Testing TimeLine Ventricular Arrhythmia base calmodulin-dependent protein kinase II design efficacy testing high risk improved in vivo in vivo Model inhibitor/antagonist insight killings molecular modeling mouse model new therapeutic target novel pre-clinical programs response sensor small molecule sudden cardiac death

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项目摘要

DESCRIPTION (provided by applicant): Ventricular arrhythmias have diverse and complex etiologies that include excessive stimulation of multiple neurohumoral pathological pathways, suggesting that no single upstream blocker will be sufficiently efficacious. Ca[2+]/calmodulin-dependent protein kinase II (CaMKII) is a common downstream mediator of these neurohumoral pathways and its hyperactivity contributes to the mechanisms of ventricular arrhythmia. We propose that the kinase is a novel therapeutic target, an idea supported by the demonstration that pharmacological and genetic reduction of CaMKII activity decreases arrhythmia in animal models and in human cardiomyocytes from patients with arrhythmia and elevated CaMKII. We have developed small molecule inhibitors of CaMKII and propose to increase potency and selectivity of the lead compound then test the best compounds for inhibition of arrhythmia in a robust mouse model. Guided by insights we developed from docking inhibitors to its active site in our new crystal structures we propose a set of compounds designed for lead optimization. Our goal is to improve potency 10-fold and reach IC50s below 15 nM. The preclinical proof-of concept study will test the in vivo efficacy of the top inhibitors using a calcineurin over expressing mouse model that is relevant to larger animal models, and likely to diseased human myocardium as well. The mice have severe heart failure and high levels of ambient arrhythmias resulting from increased CaMKII expression and our milestone is to show efficacy with at least one CaMKII inhibitor. If successful we will be positioned to extend the preclinical development by optimizing the inhibitors for ADME/Tox and other drug-like properties, testing their efficacy in other animal models, and perform IND enabling studies for an IND application aimed at arrhythmia in heart failure. PUBLIC HEALTH RELEVANCE: Sudden cardiac death is a major public health problem, which is estimated to kill 500,000 Americans each year. Most sudden cardiac death is due to rapid ventricular arrhythmias and patients with heart failure are at highest risk. Evidence now supports that pharmacological targeting of intracellular signaling, in particular of Ca2+/calmodulin-dependent protein kinase II, a sensor of dysregulated calcium homeostasis, will inhibit arrhythmia in heart failure, and it is thus a novel target in arrhythmia. We propose to modify a small molecule inhibitor we developed for this protein kinase in ways that increase its potency, analyze the new inhibitors biochemically to ensure they have the desired properties, and then test for inhibition of arrhythmia in a mouse model as a proof-of-concept.

描述（由申请人提供）：心室心律不齐具有多种多样且复杂的病因，包括过度刺激多个神经肿瘤病理途径，这表明没有任何单个上游阻滞剂将足够有效。 Ca [2+]/钙调蛋白依赖性蛋白激酶II（CAMKII）是这些神经肿瘤途径的常见下游介体，其多动作用有助于心室心律失常的机制。我们建议这种激酶是一个新型的治疗靶标，这是通过证明CAMKII活性的药理学和遗传降低降低动物模型中心律不齐和人类心律不齐患者和CAMKII升高的人类心肌细胞的想法的支持。我们已经开发了CAMKII的小分子抑制剂，并提出提高铅化合物的效力和选择性，然后测试最佳的化合物，以抑制心律不齐的小鼠模型。在我们的新晶体结构中，我们从对接抑制剂到其活跃位点的洞察力为指导，我们提出了一组设计用于铅优化的化合物。我们的目标是提高效力10倍，并达到15 nm以下的IC50。临床前概念证明研究将使用钙调蛋白比表达的小鼠模型测试顶部抑制剂的体内疗效，该模型与较大的动物模型有关，并且可能也患有人类心肌。小鼠患有严重的心力衰竭和高水平的环境心律不齐，导致CAMKII表达增加，我们的里程碑是至少一种CAMKII抑制剂表现出疗效。如果成功的话，我们将通过优化ADME/TOX和其他类似药物的抑制剂来扩展临床前开发，从而测试其在其他动物模型，并对针对心律失常的IND应用进行IND促进研究。公共卫生相关性：猝死是一个主要的公共卫生问题，估计每年将杀死50万美国人。大多数心脏猝死是由于心律不齐的快速和心力衰竭患者的风险最高。现在，有证据支持细胞内信号传导的药理靶向，特别是Ca2+/钙调蛋白依赖性蛋白激酶II（一种失调的钙稳态失调的传感器），会抑制心律失常的心力衰竭，因此它是心律失常中的新靶标。我们建议以增加其效力的方式来修改我们为这种蛋白激酶开发的小分子抑制剂，分析新的抑制剂生物化学以确保它们具有所需的特性，然后测试小鼠模型中心律失常的抑制作用作为验证。