Targeting CaM Kinase II and Oxidative Damage in Allergic Asthma

针对过敏性哮喘中的 CaM 激酶 II 和氧化损伤

• 批准号: 8201775
• 负责人: Howard Schulman
• 金额: $ 24.92万
• 依托单位: ALLOSTEROS THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8201775
• 关键词: Active Sites; Adult; Affect; American; Amplifiers; Asthma; Binding; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium/calmodulin-dependent protein kinase; Calmodulin; Chemicals; Child; Clinical; Development; Disease; Disease Pathway; Docking; Epithelial Cells; Extrinsic asthma; Functional disorder; Genetic; Glucocorticoids; Goals; Goblet Cells; Grant; Health; Human; In Situ; Inflammation; Inhibitory Concentration 50; Lead; Lung; Lung diseases; Mediator of activation protein; Metaplasia; Modeling; Monitor; Mucous body substance; Muscle Contraction; Obstruction; Ovalbumin; Oxidation-Reduction; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phenotype; Phosphotransferases; Positioning Attribute; Property; Public Health; Reactive Oxygen Species; Reliance; Respiratory physiology; Series; Site; Smooth Muscle; Stimulus; Structure; Structure-Activity Relationship; Testing; Therapeutic; TimeLine; airway hyperresponsiveness; allergic response; analog; base; bronchial epithelium; calmodulin-dependent protein kinase II; design; disease phenotype; effective therapy; efficacy testing; enzyme structure; improved; in vivo Model; inhibitor/antagonist; innovation; insight; mouse model; novel; oxidation; oxidative damage; pre-clinical; response; sensor; small molecule

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.

描述（由申请人提供）：哮喘是一个主要的公共卫生问题，影响了美国的2500万美国成年人和儿童以及全球超过3亿人。它的特征是由于支气管平滑肌收缩而引起的可逆气流阻塞以及气道高反应性（AHR）的患病上皮细胞表型，对环境刺激，增加了杯状细胞的增加，并增加了腔内粘液的分泌。过敏反应与支气管上皮中的活性氧（ROS）的增加有关，该物种是在支撑和促进上皮细胞功能障碍之前的。对疾病的修饰疗法的需求未满足，可以通过靶向氧化损伤的途径来降低对糖皮质激素的依赖。我们最近的研究位置Ca2 ？？？ （CAM）依赖性蛋白激酶II（CAMKII）作为哮喘中病理ROS反应的关键传感器，放大器和介体。我们旨在根据CAMKII晶体结构的新见解来优化CAMKII的小分子抑制剂，从而改善其类似药物的特性。我们将增加其效力，然后在经过验证的过敏性哮喘的小鼠模型中测试铅化合物。我们的第一阶段目标是进行足够的铅优化，以进行临床前的概念概念，即CAMKII抑制会抑制AHR和其他哮喘表型。我们已经根据酶的新晶体结构设计了抑制剂，这些抑制剂与先验SAR一起表明了它如何结合激酶并鉴定新化合物可以与之相互作用的附近残基，从而产生更有效和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的椭圆蛋白小鼠模型中测试功效，监测其在AHR，杯状细胞化生和粘液分泌中的疗效。这种以前无法识别的疾病途径为哮喘提供了一种新颖而创新的治疗机会。我们的整体I阶段目标是测试卵蛋白模型中改进的铅化合物，如果成功将证明II期提案是合理的，以优化铅化合物的药物样性能，并执行ADME/TOX和其他所需的研究以达到IND。 公共卫生相关性：哮喘是影响美国2500万美国成年人和全球超过3亿人的主要公共卫生问题。气道对环境刺激的过度反应性和腔内粘液分泌增加的肺功能和疾病表型的降低，先于支气管上皮的氧化和炎症。我们最近的研究暗示了Ca2 ????依赖性蛋白激酶II（CAMKII）是哮喘中病理氧化和炎症的关键传感器，放大器和介体。我们旨在根据其结构的新见解来优化CAMKII的小分子抑制剂，以填补对疾病修饰疗法的未满足需求，从而可以通过靶向氧化损伤的途径来减少对糖皮质激素的依赖。