Targeting CaM Kinase II and Oxidative Damage in Allergic Asthma

描述(申请人提供)：哮喘是一个主要的公共卫生问题，在美国影响着2500万美国成年人和儿童，在全球超过3亿人。其特点是由支气管平滑肌收缩引起的可逆性气流阻塞和对环境刺激的呼吸道高反应性(AHR)的病变上皮细胞表型，杯状细胞增加，腔粘液分泌增加。过敏性反应与支气管上皮中活性氧簇(ROS)的增加有关，这是上皮细胞功能障碍的先兆和促进因素。有一个尚未满足的疾病修改疗法的需求，减少对糖皮质激素的依赖，潜在地通过靶向氧化损伤的途径。我们最近的研究定位了钙？(CaM)依赖的蛋白激酶II(CaMKII)是哮喘病理性ROS反应的关键感受器、放大器和介体。我们的目标是基于对CaMKII晶体结构的新见解来优化CaMKII的小分子抑制剂，从而提高其类药物性能。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上测试我们的先导化合物。我们第一阶段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，即CaMKII抑制抑制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一起表明了它是如何与激酶结合的，并识别了新化合物可以与之相互作用的附近残基，以产生更有效、更具选择性的抑制剂。然后将测试优化的铅抑制剂在过敏性哮喘卵蛋白小鼠模型中的有效性，监测其在AHR、杯状细胞化生和粘液分泌方面的有效性。这一以前未被认识到的疾病途径为哮喘提供了新的和创新的治疗机会。我们第一阶段的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类药物特性，并执行ADME/Tox和其他必要的研究，以达到IND。 公共卫生相关性：哮喘是一个主要的公共卫生问题，影响着美国2500万成年人和儿童以及全球超过3亿人。肺功能下降和呼吸道对环境刺激的高反应性和腔粘液分泌增加的疾病表型先于支气管上皮的氧化和炎症。我们最近的研究表明，钙依赖的蛋白激酶II(CaMKII)是哮喘病理性氧化和炎症的关键感受器、放大器和介体。我们的目标是基于对CaMKII结构的新见解来优化CaMKII的小分子抑制剂，以满足疾病修改治疗的未满足需求，以减少对糖皮质激素的依赖，可能通过靶向氧化损伤的途径。

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.