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

Abstract

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. For prophylactic evaluation, AQX-1125 (3, 10 or 30mg·kg-1 ·d-1 , p.o.) or dexamethasone (1mg·kg-1 ·d-1 , i.p.) were given to CD-1 mice starting 3days before intratracheal administration of bleomycin (0.1IU per mouse) and continued daily for 7 or 21 days. Therapeutic potentials of AQX-1125 (3, 10 or 30mg·kg-1 ·d-1 , p.o.) or pirfenidone (90mg·kg-1 ·d-1 , p.o.) were assessed by initiating treatment 13days after bleomycin instillation and continuing until day 28. Given prophylactically, AQX-1125 (10 and 30mg·kg-1 ) reduced histopathological changes in lungs, 7 and 21days 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 30mg·kg-1 ) improved lung histopathology, cellular infiltration and reduced lung collagen content. At 30mg·kg-1 , the effects of AQX-1125 were similar to those of pirfenidone (90mg·kg-1 ) with corresponding improvements in disease severity. 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.