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

• 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
• 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

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）：室性心律失常具有多种复杂的病因，包括多种神经体液病理通路的过度刺激，表明单一上游阻滞剂不会充分有效。Ca[2+]/钙调蛋白依赖性蛋白激酶II（CaMKII）是这些神经体液通路的共同下游介质，其过度活跃有助于室性心律失常的机制。我们建议激酶是一种新的治疗靶点，这一想法得到了以下证据的支持：药理学和遗传学上降低CaMKII活性可降低动物模型和心律失常患者的人心肌细胞中的心律失常和CaMKII升高。我们已经开发了CaMKII的小分子抑制剂，并建议增加先导化合物的效力和选择性，然后在稳健的小鼠模型中测试抑制心律失常的最佳化合物。我们从对接抑制剂开发到其在我们的新晶体结构中的活性位点的见解的指导下，我们提出了一组设计用于铅优化的化合物。我们的目标是将效力提高10倍，并达到低于15 nM的IC 50。临床前概念验证研究将使用钙调磷酸酶过表达小鼠模型测试顶级抑制剂的体内功效，该模型与较大的动物模型相关，并且也可能与患病的人类心肌相关。小鼠具有由CaMKII表达增加引起的严重心力衰竭和高水平的环境性心律失常，并且我们的里程碑是显示至少一种CaMKII抑制剂的功效。如果成功，我们将通过优化ADME/Tox抑制剂和其他药物样特性，测试其在以下方面的功效， 其他动物模型，并进行IND使能研究，用于IND应用，旨在治疗心力衰竭中的心律失常。 心脏性猝死是一个主要的公共卫生问题，据估计每年有50万美国人死于心脏性猝死。大多数心脏性猝死是由于快速室性心律失常，心力衰竭患者的风险最高。现在的证据支持，药理学靶向细胞内信号，特别是钙/钙调蛋白依赖性蛋白激酶II，钙稳态失调的传感器，将抑制心力衰竭的心律失常，因此它是心律失常的一个新的目标。我们建议修改我们为这种蛋白激酶开发的小分子抑制剂，以提高其效力，对新的抑制剂进行生物化学分析，以确保它们具有所需的特性，然后在小鼠模型中测试心律失常的抑制作用，作为概念验证。