PT - JOURNAL ARTICLE AU - Kasiviswanath Routhu AU - Kanthikiran Varanasi AU - Sridhar Veeraraghavan AU - Meyyappan Muthuppalaniappan AU - G. Babu AU - Srikant Viswanadha AU - Swaroop Vakkalanka TI - Late-breaking abstract: Pre-clinical efficacy of RP5090 in PI3Kδ mediated airway disorders DP - 2011 Sep 01 TA - European Respiratory Journal PG - 4495 VI - 38 IP - Suppl 55 4099 - http://erj.ersjournals.com/content/38/Suppl_55/4495.short 4100 - http://erj.ersjournals.com/content/38/Suppl_55/4495.full SO - Eur Respir J2011 Sep 01; 38 AB - Introduction: PI3Kδ plays a pivotal role in airway remodelling processes that include recruitment and activation of inflammatory cells, cytokine release, mast cell activation and vascular permeability. Given the established criticality of PI3Kδ in airway inflammation, inhibitors specifically targeting this isoform would attenuate progression of asthma and COPD.Methods: Specificity of RP5090 towards PI3Kδ, suppression of pAKT in THP-1 cells, elastase exocytosis and migration in neutrophils, and IgE-induced mast cell degranulation were determined. Pre-clinical efficacy of RP5090 was confirmed in animal models of airway disorders, namely, LPS-induced pulmonary neutrophilia in rat as well as in acute and chronic eosinophilia models in Guinea Pig.Results: RP5090 demonstrated significant potency against PI3Kδ (18.5 nM) with several fold selectivity over other isoforms with subsequent inhibition of pAKT. Additionally, the compound inhibited neutrophil functionality and mast-cell degranulation at nanomolar concentrations. RP5090 displayed excellent efficacy in inhibiting LPS-induced neutrophilia in SD rat (65% at 20 mg/kg b.wt). Besides, the compound decreased eosinophil infiltration into the lungs upon induction by PAF (>80% @ 10 mg/kg) or OVA (>60% @ 1 mg/kg) in Guinea pigs. Consistent with in vitro findings, the compound caused a significant inhibition of mast cell degranulation manifested by a reduction in histamine release.Conclusions: Results demonstrate the therapeutic potential of RP5090 in asthma and related airway disorders acting via the PI3Kδ pathway. Further in vivo studies are in progress to evaluate the efficacy of the compound in airway hyper-responsiveness prior to the initiation of clinical trials.