Novel signal transduction modulators for the treatment of airway diseases

Abstract

Multiple signal transduction pathways are involved in the inflammatory process in the airways of patients with asthma and chronic obstructive pulmonary disease (COPD), hence modulators of these pathways may result in novel anti-inflammatory treatments. The advantage of this approach is that these pathways are activated in many inflammatory and structural cells of the airways, hence a broad spectrum of anti-inflammatory effects may be possible. However, this also makes it more likely that side effects may be limiting, but this may not be a problem if the signal transduction pathway is selectively activated in disease and the therapeutic index may be increased by inhaled delivery. Phosphodiesterase-4 (PDE4) inhibitors are the most advanced treatment in this category as anti-inflammatory treatment for asthma and COPD, although side effects are dose limiting. Other promising approaches are inhibitors of p38 mitogen-activated protein (MAP) kinase, inhibitor of nuclear factor-kappaB kinase-2 (IKK2), and Syk kinase, all of which are in clinical development. Several other kinases and transcription factors are also targets for novel drug development. It is likely that modulators of signal transduction pathways may lead to the development of several novel anti-inflammatory treatments for asthma and COPD in the future.