Targeting CaM Kinase II and Oxidative Damage in Allergic Asthma

描述（由申请人提供）：哮喘是影响美国2500万成人和儿童以及全球超过3亿人的主要公共卫生问题。其特征是支气管平滑肌收缩引起的可逆性气流阻塞和气道对环境刺激的高反应性（AHR）病变上皮细胞表型，杯状细胞增加，管腔粘液分泌增加。过敏反应与支气管上皮活性氧（ROS）的增加有关，ROS先于并促进上皮细胞功能障碍。目前对减少对糖皮质激素依赖的疾病修饰治疗的需求尚未得到满足，可能通过靶向氧化损伤途径来实现。我们最近的研究表明Ca2???？（CaM）依赖性蛋白激酶II （CaMKII）作为哮喘病理性ROS反应的关键传感器、放大器和介质。我们的目标是基于CaMKII晶体结构的新见解来优化CaMKII的小分子抑制剂，从而提高其药物样性质。我们将提高其效力，然后在经过验证的过敏性哮喘小鼠模型中测试我们的先导化合物。我们I期的总体目标是进行充分的先导优化，以进行临床前概念验证，证明CaMKII抑制可以抑制AHR和其他哮喘表型。我们根据酶的新晶体结构设计了抑制剂，与先前的SAR一起表明它如何结合激酶并识别新化合物可以与之相互作用的附近残基，以产生更有效和更有选择性的抑制剂。优化后的铅抑制剂将在过敏性哮喘卵清蛋白小鼠模型中进行疗效测试，监测其对AHR、杯状细胞化生和粘膜分泌的疗效。这种以前未被认识的疾病途径为哮喘提供了一种新颖和创新的治疗机会。我们的第一阶段总体目标是在卵清蛋白模型中测试一种改进的先导化合物，如果成功，将证明第二阶段的建议是合理的，以优化先导化合物的药物样特性，并进行ADME/Tox和其他必要的研究，以达到IND。

DESCRIPTION (provided by applicant): Asthma is a major public health problem affecting 25 million American adults and children in the US and over 300 million people globally. It is characterized by reversible airflow obstruction due to bronchial smooth muscle contraction and a diseased epithelial cell phenotype of airway hyper-reactivity (AHR) to environmental stimuli, increase in goblet cell, and increased luminal mucous secretion. The allergic response is associated with an increase in reactive oxygen species (ROS) in bronchial epithelium that precedes and promotes epithelial cell dysfunction. There is an unmet need for disease modifying therapy that reduces reliance on glucocorticoids, potentially by targeting pathways of oxidative damage. Our recent studies position Ca2???? (CaM)-dependent protein kinase II (CaMKII) as a key sensor, amplifier, and mediator of pathological ROS responses in asthma. We aim to optimize a small molecule inhibitor of CaMKII based on new insights from CaMKII crystal structures and thereby improve its drug-like properties. We will increase its potency and then test our lead compound in a validated mouse model of allergic asthma. Our overall goals for Phase I are to perform sufficient lead optimization to conduct a pre-clinical proof-of-concept that CaMKII inhibition suppresses AHR and other asthma phenotypes. We have designed inhibitors based on new crystal structure of the enzyme that together with prior SAR suggests how it binds the kinase and identifies nearby residues that new compounds can interact with to produce more potent and more selective inhibitors. Optimized lead inhibitors will then be tested for efficacy in the ovalbumin mouse model of allergic asthma, monitoring its efficacy in AHR, goblet cell metaplasia, and mucous secretion. This previously unrecognized disease pathway offers a novel and innovative therapeutic opportunity for asthma. Our overall Phase I aim is to test an improved lead compound in the ovalbumin model, that if successful would justify a Phase II proposal to optimize drug-like properties of the lead compound and perform the ADME/Tox and other studies necessary to reach IND. PUBLIC HEALTH RELEVANCE: Asthma is a major public health problem affecting 25 million American adults and children in the US and over 300 million people globally. The reduced lung function and disease phenotype of airway hyper-reactivity to environmental stimuli and increased luminal mucous secretion is preceded by oxidation and inflammation of bronchial epithelium. Our recent studies implicate Ca2????dependent protein kinase II (CaMKII) as a key sensor, amplifier, and mediator of pathological oxidation and inflammation in asthma. We aim to optimize a small molecule inhibitor of CaMKII based on new insights of its structure to fill an unmet need for disease modifying therapy that reduces reliance on glucocorticoids, potentially by targeting pathways of oxidative damage.