Phosphatidylinositol 3-kinases (PI3Ks) are key elements in the signaling cascades that lie downstream of many cellular receptors. In particular, PI3K delta and gamma
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,
TG100-115 [3-[2,4-diamino-6-(3-hydroxyphenyl)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 delta and gamma are suitable molecular targets for these diseases.