Pre-clinical efficacy of dual PI3K δ/γ inhibitors in airway inflammation (64.2)

Abstract

Abstract Dual δ/γ inhibition is strongly implicated as an intervention treatment in allergic and non-allergic inflammation of the airways and autoimmune diseases. The objective of this study was to explore the therapeutic potential of RP6047, a novel, small molecule PI3Kδ/γ inhibitor in airway disorders. Specificity of lead molecule, RP6047, towards PI3Kδ and γ isoforms and subsequent downstream activity was determined in enzyme and several cell based assays. Pre-clinical efficacy of RP6047 was confirmed in animal models of airway inflammation. RP6047 demonstrated significant potency against PI3Kδ (19.7 nM) and γ (31.2 nM) with several fold selectivity over α and β isoforms and subsequent pAKT inhibition. Additionally, the compound inhibited neutrophil functionality and mast-cell degranulation at nanomolar concentrations besides reversing CSE induced dexamethasone insensitivity by >90%. RP6047 displayed excellent efficacy in inhibiting LPS-induced TNFα (36% at 10 mg/kg/po) and neutrophilia (ED50 = 1.35 mg/kg/po) in a rat model. Administration of compound also resulted in a near complete reduction in inflammatory cell infiltration into the lungs in CSE treated mice over a 4-day period. Results demonstrate the therapeutic potential of RP6047 in asthma and related airway disorders acting via the PI3Kδ/γ 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.