The airway is the focus of two highly prevalent diseases, COPD (chronic obstructive bronchitis and emphysema) and asthma. There is a pressing need to develop new therapeutics for COPD, particularly those that control the underlying and largely untreatable inflammatory and destructive processes that cause its relentless progression.  Worldwide, 600 million people suffer from COPD, with some three million dying from the disease each year representing a global market of US$2.8 billion. Asthma is also very common, affecting 155 million people worldwide. In the United States alone there has been a recent two-fold increase in the number of cases of asthma driving pharmaceutical market values up to as high as $8 billion worldwide. Despite a large number of drugs available to clinicians, up to 15% of patients suffer from uncontrollable disease symptoms, increasing the demand for novel therapies that possess new modes of action.

Although they involve different cell types, asthma and COPD are both chronic inflammatory diseases associated with cellular infiltration and activation. These processes are induced by overexpression of various chemokines and cytokines, downstream targets for activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB), transcription factors that are themselves elevated in asthma. There is increasing evidence that synergistic interaction of these transcription factors results in the optimal expression of target genes, resulting in the specific inflammatory pattern seen in asthmatic airways. Hence transcription factors are a target for anti-asthma therapy.

Glucocorticoids are the most effective anti-inflammatory drugs used in the treatment of chronic inflammatory diseases such as asthma. They act by binding to a specific glucocorticoid receptor that on activation translocates to the nucleus and controls expression of responsive genes. The ability of the transcription factors AP-1 and NF-kappaB to induce gene transcription is attenuated by glucocorticoid receptors. Although only 5-10% of asthmatic subjects are glucocorticoid-insensitive, these subjects account for over 50% of the health-care costs for asthma. Systemic corticosteroids are also routinely used for the treatment of acute exacerbation of COPD and inhaled corticosteroids are increasingly prescribed for the long-term treatment of patients. However the therapeutic efficacy of corticosteroids in COPD remains unproven and limited efficacy may be due in part to corticosteroid resistance. The development of small molecule therapies that interfere directly with AP-1 transcription may therefore be of benefit in corticosteroid resistant airway disease.

Recently Seattle-based researchers have addressed this issue using a chemogenomics approach to screen for small molecule inhibitor(s) of AP-1 transcription. Using this approach a small-molecule inhibitor, PNRI-299, was identified that selectively inhibited AP-1 transcription without affecting NF-kappaB transcription. This effect was suggested to involve the inhibition of redox factor 1 (Ref-1), a nuclear factor that regulates AP-1 transcription. PNRI-299 significantly reduced airway eosinophil infiltration, mucus hypersecretion, edema, and IL-4 levels in a mouse asthma model. These data validate AP-1 as an important therapeutic target in allergic airway inflammation and molecules such as PNRI-299 may therefore be of use in the treatment of asthma. The therapeutic efficacy of AP-1 inhibition in the treatment of COPD remains to be seen.

Entry date February, 2003

Adapted from Nguyen et al, Proc Natl Acad Sci U S A 2003 Jan 24; [epub ahead of print] - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk