New STAT6 inhibitors with potential therapeutic application in asthma (37.1)

Abstract

Abstract Asthma is an inflammatory disease that represents an important health problem. The origin of this disease seems to be due to an immunological anomalous response to apparently innocuous antigens. In the last years, an important number of molecular intermediaries have been found to be implicated in the progression of this disease. The importance of these mediators is determined by the fact that they are actively being investigated as potential therapeutic targets. In this regard, numerous evidences indicate that Interleuquina-4 (IL-4) and IL-13 have a central role in the development of asthma through the activation of the factor of transcription STAT6. In a previous study, our group demonstrated that antiinflammatory doses of salicylates inhibited the activation of this factor of transcription. The objective of the present study was to obtain new inhibitors of STAT6 derived from salicylates by performing sequential chemical modifications. With this approach, we obtained several compounds with a planar and rigid structure, and a specific pattern of hydroxyl groups that were able to inhibit the activation of STAT6 with great efficiency. Among the obtained compounds, the named JRC688 and JRC706 inhibited the activation of STAT6 at concentrations of 20 μM. To investigate the effect of these compounds in asthma, we chose JRC706 since it had little effect on cell viability, suggesting it could have less undesirable effects. The found results indicate that the administration of JRC706 could prevent the inflammatory response in asthma. Thus, infiltrated inflammatory cells in lung and bronchoalveolar fluids, mucus production, hyperplasia of globet cells, and levels of IgE were greatly diminished in mice treated with JRC706 with regard to untreated asthmatic controls. These findings indicate that JRC706 is a good compound to investigate in asthma.