TG100–115, a PI3 Kinase γ/δ Inhibitor, Reduces Lung Inflammation and Airway Hyperresponsiveness in a Mouse Asthma Model

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Rationale: The γ and δ isoforms of phosphoinositide 3‐kinase (PI3K) regulate immune/inflammatory responses by multiple cell types including Th2 T cells, mast cells, and eosinophils. We explored whether a dual PI3K γ/δ inhibitor could impact airway hyperresponsiveness (AHR) and inflammation.Methods: Mice were sensitized with ovalbumin (OVA) on Day 0 and boosted on Day 5, followed by inhalation challenges on Days 12–13. TG100–115, a PI3K γ/δ inhibitor (IC50 = 83 and 235 nM, respectively), was delivered by inhalation on Days 11–14 for total daily doses of 100 mg/kg; dexamethasone (DEX) was delivered at 3 mg/kg i.p on Days 8–14. On Day 15, AHR was determined following aerosolized methacholine (MC) challenge, polymorphonuclear (PMN) cell counts were determined from bronchoalveolar lavage fluid (BALF), and lungs were processed for histology.Results: Exposure to aerosolized TG100–115 resulted in sustained compound levels within the lung and airways with minimal plasma exposure. TG100–115 reduced both AHR and PMN accumulation vs. vehicle‐treated animals, to near maximal response of systemic DEX. Histology showed that both treatments reduced inflammation and mucin accumulation to near background levels.Conclusion: An aerosolized PI3K γ/δ inhibitor reduces asthma symptoms in a standard mouse model, and may represent a new anti‐inflammatory therapy for future clinical exploration.