Kinase targets and inhibitors for the treatment of airway inflammatory diseases: the next generation of drugs for severe asthma and COPD?

Abstract

Kinases are believed to play a crucial role in the expression and activation of inflammatory mediators in the airway, in T-cell function, and in airway remodeling. Important pro-inflammatory transcription factors such as activating protein-1 and nuclear factor kappaB, which are activated in airway disease, require kinase activation to switch on inflammatory genes, while other kinases can regulate mRNA half-life. Selective kinase inhibitors have been developed that reduce inflammatory gene expression and some characteristics of disease in animal models. Targeting specific kinases that are overexpressed or overactive in disease should allow for selective treatment of airway inflammatory diseases. Interest in this area has intensified due to the success of the specific Abelson murine leukemia viral oncogene homolog tyrosine kinase inhibitor, imatinib mesylate, in the treatment of chronic myelogenous leukemia. Encouraging data from animal models and primary cells and early phase I and II studies in other diseases suggest that inhibitors of p38 mitogen-activated protein kinase and inhibitor of kappaB kinase-2 may prove to be useful novel therapies in the treatment of severe asthma and chronic obstructive pulmonary disease.