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

描述（由申请方提供）：当心输出量不足以满足代谢要求时，心脏病转化为心力衰竭的临床综合征。现在的证据支持药理学靶向钙离子依赖性蛋白激酶II（CaMKII），钙稳态失调的传感器，将抑制细胞病理生理学的早期阶段向有症状的心力衰竭和猝死的转化。用研究抑制剂抑制激酶，或通过基因敲除主要的心脏亚型，阻断了动物模型中的这一事件链。我们提出了一种策略，修改CaMKII的小分子抑制剂，以增加其效力和选择性，测试它的生化，以确保它具有所需的作用机制，然后测试抑制肥大的特征标记物和新生小鼠心肌细胞的凋亡。我们从一种用于证明其心血管功能的变构CaMKII抑制剂开始，但从未进行过优化，因此效力较低。通过我们对新晶体结构和结构见解的分析，我们已经从对接抑制剂开发到其活性位点，我们设计了一组化合物，这些化合物针对CaMKII活性位点中变构口袋的独特功能。我们I期的总体目标是保持和提高抑制剂的选择性，同时显著提高其效力，并测试先导抑制剂化合物的功效，然后测试其对肥大的特征性标志物的抑制以及新生小鼠心肌细胞的凋亡 公共卫生相关性：心力衰竭是一个全球性负担，在发达国家的终生风险超过20%，是患者、临床医生、科学家和政策制定者关注的焦点。当心输出量不足以满足代谢要求时，心脏病转化为心力衰竭的临床综合征。现在的证据支持，药理学靶向细胞内信号，特别是钙离子？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，以增加其效力的方式修改这种蛋白激酶的小分子抑制剂，对其进行生物化学分析以确保其具有所需的作用机制，然后测试其在新生小鼠心肌细胞中抑制肥大的特征性标志物和凋亡。

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.