Progress in the development of kinase inhibitors for treating asthma and COPD

Abstract

Current therapies to mitigate inflammatory responses involved in airway remodeling and associated pathological features of asthma and chronic obstructive pulmonary disease (COPD) are limited and largely ineffective. Inflammation and the release of cytokines and growth factors activate kinase signaling pathways that mediate changes in airway mesenchymal cells such as airway smooth muscle cells and lung fibroblasts. Proliferative and secretory changes in mesenchymal cells exacerbate the inflammatory response and promote airway remodeling, which is often characterized by increased airway smooth muscle mass, airway hyperreactivity, increased mucus secretion, and lung fibrosis. Thus, inhibition of relevant kinases has been viewed as a potential therapeutic approach to mitigate the debilitating and, thus far, irreversible airway remodeling that occurs in asthma and COPD. Despite FDA approval of several kinase inhibitors for the treatment of proliferative disorders, such as cancer and inflammation associated with rheumatoid arthritis and ulcerative colitis, none of these drugs have been approved to treat asthma or COPD. This review will provide a brief overview of the role kinases play in the pathology of asthma and COPD and an update on the status of kinase inhibitors currently in clinical trials for the treatment of obstructive pulmonary disease. In addition, potential issues associated with the current kinase inhibitors, which have limited their success as therapeutic agents in treating asthma or COPD, and alternative approaches to target kinase functions will be discussed.

Keywords: Airway remodeling; Asthma; Chronic obstructive pulmonary disease; Inflammation; Kinase inhibitors; Pulmonary disease; Signal transduction.