Characterization of AQX-1125, a small-molecule SHIP1 activator Part 2. Efficacy studies in allergic and pulmonary inflammation models in vivo

Grant R. Stenton, Lloyd F. MacKenzie, Patrick Tam, Jennifer L. Cross, Curtis Harwig, Jeffrey Raymond, Judy Toews, David Chernoff, Thomas MacRury, Csaba Szabo

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Background The efficacy of AQX-1125, a small-molecule SH2-containing inositol-5′-phosphatase 1 (SHIP1) activator and clinical development candidate, is investigated in rodent models of inflammation. Experimental Approach AQX-1125 was administered orally in a mouse model of passive cutaneous anaphylaxis (PCA) and a number of rodent models of respiratory inflammation including: cigarette smoke, LPS and ovalbumin (OVA)-mediated airway inflammation. SHIP1 dependency of the AQX-1125 mechanism of action was investigated by comparing the efficacy in wild-type and SHIP1-deficient mice subjected to an intrapulmonary LPS challenge. Results AQX-1125 exerted anti-inflammatory effects in all of the models studied. AQX-1125 decreased the PCA response at all doses tested. Using bronchoalveolar lavage (BAL) cell counts as an end point, oral or aerosolized AQX-1125 dose dependently decreased the LPS-mediated pulmonary neutrophilic infiltration at 3-30 mg kg-1 and 0.15-15 μg kg-1 respectively. AQX-1125 suppressed the OVA-mediated airway inflammation at 0.1-10 mg kg-1. In the smoke-induced airway inflammation model, AQX-1125 was tested at 30 mg kg-1 and significantly reduced the neutrophil infiltration of the BAL fluid. AQX-1125 (10 mg kg-1) decreased LPS-induced pulmonary neutrophilia in wild-type mice but not in SHIP1-deficient mice. Conclusions The SHIP1 activator, AQX-1125, suppresses leukocyte accumulation and inflammatory mediator release in rodent models of pulmonary inflammation and allergy. As shown in the mouse model of LPS-induced lung inflammation, the efficacy of the compound is dependent on the presence of SHIP1. Pharmacological SHIP1 activation may have clinical potential for the treatment of pulmonary inflammatory diseases. Linked Article This article is accompanied by Stenton et al., pp. 1506-1518 of this issue. To view this article visit http://dx.doi.org/10.1111/bph.12039

Original languageEnglish (US)
Pages (from-to)1519-1529
Number of pages11
JournalBritish Journal of Pharmacology
Volume168
Issue number6
DOIs
StatePublished - Mar 2013
Externally publishedYes

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Keywords

  • asthma
  • chemotaxis
  • COPD
  • inflammation
  • PI3K
  • pulmonary
  • SHIP1

ASJC Scopus subject areas

  • Pharmacology

Cite this

Stenton, G. R., MacKenzie, L. F., Tam, P., Cross, J. L., Harwig, C., Raymond, J., Toews, J., Chernoff, D., MacRury, T., & Szabo, C. (2013). Characterization of AQX-1125, a small-molecule SHIP1 activator Part 2. Efficacy studies in allergic and pulmonary inflammation models in vivo. British Journal of Pharmacology, 168(6), 1519-1529. https://doi.org/10.1111/bph.12038