Targeting CaM Kinase II and Oxidative Damage in Allergic Asthma

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 newcompounds 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 mucoussecretion. 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 theUS 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 tofill an unmet need for disease modifying therapy that reduces reliance on glucocorticoids, potentially by targeting pathways of oxidative damage.