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

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，这表明没有单一的上游阻滞剂足够有效。Ca[2+]/钙调素依赖性蛋白激酶II （CaMKII）是这些神经体液通路的常见下游介质，其高活性有助于室性心律失常的机制。我们提出该激酶是一个新的治疗靶点，这一观点得到了CaMKII活性的药理学和遗传学降低动物模型和心律失常患者和CaMKII升高的人心肌细胞中心律失常的证明的支持。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，然后在健壮的小鼠模型中测试最佳化合物对心律失常的抑制作用。根据我们从对接抑制剂到新晶体结构中活性位点的见解，我们提出了一组用于先导优化的化合物。我们的目标是将效力提高10倍，并使ic50低于15 nM。临床前概念验证研究将使用钙调磷酸酶过表达的小鼠模型来测试顶级抑制剂的体内功效，该模型与更大的动物模型相关，并且可能也适用于患病的人类心肌。由于CaMKII表达增加，小鼠有严重的心力衰竭和高水平的环境性心律失常，我们的里程碑是显示至少一种CaMKII抑制剂的疗效。如果成功，我们将通过优化ADME/Tox抑制剂和其他类似药物的特性来扩展临床前开发，测试它们在

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.