AQX-1125, small molecule SHIP1 activator inhibits bleomycin-induced pulmonary fibrosis.

Abstract

BACKGROUND AND PURPOSE:

The phosphatase SHIP1 negatively regulates the PI3K pathway, and its predominant expression within cells of the haematopoietic compartment makes SHIP1 activation a novel strategy to limit inflammatory signalling generated through PI3K. AQX-1125 is the only clinical-stage, orally administered, SHIP1 activator. Here, we demonstrate the prophylactic and therapeutic effects of AQX-1125, in a mouse model of bleomycin-induced lung fibrosis.

EXPERIMENTAL APPROACH:

For prophylactic evaluation, AQX-1125 (3, 10 or 30 mg·kg-1 ·d-1 , p.o.) or dexamethasone (1 mg·kg-1 ·d-1 , i.p.) were given to CD-1 mice starting 3 days before intratracheal administration of bleomycin (0.1 IU per mouse) and continued daily for 7 or 21 days. Therapeutic potentials of AQX-1125 (3, 10 or 30 mg·kg-1 ·d-1 , p.o.) or pirfenidone (90 mg·kg-1 ·d-1 , p.o.) were assessed by initiating treatment 13 days after bleomycin instillation and continuing until day 28.

KEY RESULTS:

Given prophylactically, AQX-1125 (10 and 30 mg·kg-1 ) reduced histopathological changes in lungs, 7 and 21 days following bleomycin-induced injury. At the same doses, AQX-1125 reduced the number of total leukocytes, neutrophil activity, TGF-β immunoreactivity and soluble collagen in lungs. Administered therapeutically, AQX-1125 (10 and 30 mg·kg-1 ) improved lung histopathology, cellular infiltration and reduced lung collagen content. At 30 mg·kg-1 , the effects of AQX-1125 were similar to those of pirfenidone (90 mg·kg-1 ) with corresponding improvements in disease severity.

CONCLUSIONS AND IMPLICATIONS:

AQX-1125 prevented bleomycin-induced lung injury during the inflammatory and fibrotic phases. AQX-1125, given therapeutically, modified disease progression and improved survival, as effectively as pirfenidone.

• Authors: Jennifer Cross, Grant R Stenton, Curtis Harwig, Csaba Szabo, Tiziana Genovese, Rosanna Di Paola, Emanuale Esposito, Salvatore Cuzzocrea, Lloyd F Mackenzie
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 174 Issue 18 Pg. 3045-3057 (Sep 2017) ISSN: 1476-5381 [Electronic] England
• PMID: 28658529 (Publication Type: Journal Article)
• Copyright: © 2017 The British Pharmacological Society.

Chemical References

• 4-(4-(aminomethyl)-7a-methyl-1-methylideneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexan-1-ol
• Cyclohexanols
• Indans
• Small Molecule Libraries
• Bleomycin
• Inpp5d protein, mouse
• Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases

Topics

• Animals
• Bleomycin (antagonists & inhibitors)
• Cyclohexanols (administration & dosage, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Indans (administration & dosage, chemistry, pharmacology)
• Inflammation (chemically induced, drug therapy, pathology)
• Male
• Mice
• Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases (metabolism)
• Pulmonary Fibrosis (chemically induced, drug therapy, pathology)
• Small Molecule Libraries (administration & dosage, chemistry, pharmacology)
• Structure-Activity Relationship