Phosphatidylinositol 3-kinases (PI3Ks) are key elements in the signaling cascades that lie downstream of many cellular receptors. In particular, PI3K ␦ and ␥ isoforms contribute to inflammatory cell recruitment and subsequent activation. For this reason, in a series of preclinical studies, we tested the potential of a recently developed small-molecule inhibitor of these two isoforms, pteridin-7-yl]phenol], as a form of anti-inflammatory therapy for respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). To determine pharmacokinetic profiles, aerosolized formulations of the drug were delivered to mice by a nose-only inhalation route, yielding high pulmonary TG100-115 levels with minimal systemic exposure. Safety assessments were favorable, with no clinical or histological changes noted after 21 days of daily dosing. In a murine asthma model, aerosolized TG100-115 markedly reduced the pulmonary eosinophilia and the concomitant interleukin-13 and mucin accumulation characteristic of this disease. As a functional benefit, interventional dosing schedules of this inhibitor also reduced airway hyper-responsiveness. To model the pulmonary neutrophilia characteristic of COPD, mice were exposed to either intranasal lipopolysaccharide or inhaled smoke. Aerosolized TG100-115 again inhibited these inflammatory patterns, most notably in the smoke model, where interventional therapy overcame the steroid-resistant nature of the pulmonary inflammation. In conclusion, aerosolized TG100-115 displays pharmacokinetic, safety, and biological activity profiles favorable for further development as a therapy for both asthma and COPD. Furthermore, these studies support the hypothesis that PI3K ␦ and ␥ are suitable molecular targets for these diseases.
Age-related macular degeneration, diabetic retinopathy, and retinal vein occlusions are complicated by neovascularization and macular edema. Multi-targeted kinase inhibitors that inhibit select growth factor receptor tyrosine kinases and/or components of their down-stream signaling cascades (such as Src kinases) are rationale treatment strategies for these disease processes. We describe the discovery and characterization of two such agents. TG100572, which inhibits Src kinases and selected receptor tyrosine kinases, induced apoptosis of proliferating endothelial cells in vitro. Systemic delivery of TG100572 in a murine model of laser-induced choroidal neovascularization (CNV) caused significant suppression of CNV, but with an associated weight loss suggestive of systemic toxicity. To minimize systemic exposure, topical delivery of TG100572 to the cornea was explored, and while substantial levels of TG100572 were achieved in the retina and choroid, superior exposure levels were achieved using TG100801, an inactive prodrug that generates TG100572 by de-esterification. Neither TG100801 nor TG100572 were detectable in plasma following topical delivery of TG100801, and adverse safety signals (such as weight loss) were not observed even with prolonged dosing schedules. Topical TG100801 significantly suppressed laser-induced CNV in mice, and reduced fluorescein leakage from the vasculature and retinal thickening measured by optical coherence tomography in a rat model or retinal vein occlusion. These data suggest that TG100801 may provide a new topically applied treatment approach for ocular neovascularization and retinal edema.
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.
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