RT Journal Article
SR Electronic
T1 Aerosolized Phosphoinositide 3-Kinase γ/δ Inhibitor TG100-115 [3-[2,4-Diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol] as a Therapeutic Candidate for Asthma and Chronic Obstructive Pulmonary Disease
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 758
OP 765
DO 10.1124/jpet.108.144311
VO 328
IS 3
A1 John Doukas
A1 Lisa Eide
A1 Karin Stebbins
A1 Adrienne Racanelli-Layton
A1 Luis Dellamary
A1 Michael Martin
A1 Elena Dneprovskaia
A1 Glenn Noronha
A1 Richard Soll
A1 Wolfgang Wrasidlo
A1 Lisette M. Acevedo
A1 David A. Cheresh
YR 2009
UL http://jpet.aspetjournals.org/content/328/3/758.abstract
AB Phosphatidylinositol 3-kinases (PI3Ks) are key elements in the signaling cascades that lie downstream of many cellular receptors. In particular, PI3K δ and γ 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 δ and γ are suitable molecular targets for these diseases. The American Society for Pharmacology and Experimental Therapeutics