RP6503, a novel and selective PI3K δ/γ inhibitor, potentiates the effect of steroids in pre-clinical models of COPD

Introduction: Current treatment regimen for COPD is majorly restricted to inhaled corticosteroids although there is not much evidence of efficiency in this disease. Accentuating the anti-COPD effects by addition of dual PI3K δ/γ inhibitors represents a novel therapeutic strategy. The objective of this study was to explore the therapeutic potential of a combination of corticosteroid and RP6503, a novel, small molecule PI3Kδ/γ inhibitor, in COPD models. Methods: Specificity of RP6503, towards PI3Kδ and γ isoforms and subsequent downstream activity was determined in enzyme and several cell based assays. Pre-clinical efficacy of the combination RP6503 and corticosteroids was determined in in vitro and in vivo models relevant for COPD. Results: RP6503 demonstrated significant potency against PI3Kδ ( 29.3 nM ) and γ ( 28.1 nM ) enzymes with selectivity over α ( >10000-fold ) and β ( >60-fold ) isoforms. Addition of 1 μM or 100 nM RP6503 resulted in potentiation of dexamethasone activity with respect to reduction in IC 50 for IL-8 release in H 2 O 2 treated human monocytic (U937) cells ( >8-fold ) as well as TGFβ treated human lung alveolar basal epithelial (A549) cells ( 5-fold ). While fluticasone (F) alone @ 55 μg/kg was ineffective in a cigarette smoke induced cellular infiltration model in Balb/c mice, combination with RP6503 resulted in a dose-dependent reduction in macrophage count upon intranasal administration ( >80% inhibition for F + 300 μg RP6503 ) . Conclusions: Data demonstrate the therapeutic potential of the combination of corticosteroids and dual PI3Kδ/γ inhibitors in airway inflammation. Combination therapy might also be useful to overcome steroid resistance in COPD.