Aerosolized phosphoinositide 3-kinase gamma/delta 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.
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.
Doukas
John
J
TargeGen, Inc., 9380 Judicial Drive, San Diego, CA 92121, USA. jdoukas@vical.com
Eide
Lisa
L
Stebbins
Karin
K
Racanelli-Layton
Adrienne
A
Dellamary
Luis
L
Martin
Michael
M
Dneprovskaia
Elena
E
Noronha
Glenn
G
Soll
Richard
R
Wrasidlo
Wolfgang
W
Acevedo
Lisette M
LM
Cheresh
David A
DA
D000281:Administration, Intranasal; D000336:Aerosols; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004195:Disease Models, Animal; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D010636:Phenols / Q000627:therapeutic use*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011621:Pteridines / Q000627:therapeutic use*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*
C539252:3-(2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl)phenol; D000336:Aerosols; D000893:Anti-Inflammatory Agents; D007527:Isoenzymes; D008070:Lipopolysaccharides; D010636:Phenols; D011621:Pteridines; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse