Characterization of AQX‐1125, a small‐molecule SHIP1 activator

Abstract

BACKGROUNDThe 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 APPROACHAQX-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. RESULTSAQX-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 mg kg -1 respectively. AQX-1125 suppressed the OVA-mediated airway inflammation at 0.1-10 mg kg ) decreased LPS-induced pulmonary neutrophilia in wild-type mice but not in SHIP1-deficient mice. CONCLUSIONSThe 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 ARTICLEThis article is accompanied by Stenton et al., pp. 1506Stenton et al., pp. -1518

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

“…CCL2 deficiency is protective in the bleomycin model (Gharaee‐Kermani et al , ), and its levels are significantly elevated in the BAL fluid of IPF patients (Suga et al , ). Although CCL2 was not measured specifically in this study, AQX‐1125 has previously been shown to be able to decrease levels of CCL2 in the BAL fluid of LPS‐mediated pulmonary inflammation in rats (Stenton et al , ). Therefore, one possible mechanism by which SHIP1 activators like AQX‐1125 could limit fibrosis is by limiting the production of profibrotic mediators that drive the recruitment of leukocytes and fibrocytes.…”

“…In vitro , AQX‐1125 suppressed chemotaxis in human neutrophils and lymphocytes and reduced pro‐inflammatory cytokine release from murine splenocytes (Stenton et al , ). Across several in vivo rodent models of pulmonary inflammation, induced by LPS, ovalbumin or cigarette smoke, AQX‐1125 consistently reduced BAL leukocyte influx (Stenton et al , ). Similarly, we have now shown that AQX‐1125 is able to reduce cellular influx and neutrophil activity in bleomycin‐induced lung injury, and this resulted in improved outcomes through the fibrotic phase (up to Day 21) including a reduction in the pro‐fibrotic mediator, TGF‐β.…”

“…The effects of AQX‐1125 were demonstrated both prophylactically and therapeutically. AQX‐1125 has good oral bioavailability, a terminal half‐life suited to once per day dosing and distributes to the lung at high concentrations (Stenton et al , ). AQX‐1125 also has a novel mechanism of action that is distinct from anti‐inflammatory compounds, such as steroids, and functions to down‐regulate the PI3K/Akt pathway without side effects of hyperglycaemia or neutropenia, as seen with PI3K inhibitors (Akinleye et al , ).…”

“…Small molecule compounds originally isolated from marine natural extracts have been found to act as activators of SHIP1, possessing anti‐inflammatory activity both in vitro and in vivo (Yang et al , ; Ong et al , ; Stenton et al , ,b). Thus, in recent years, pharmacological activation of SHIP1 has emerged as a novel approach for the experimental therapy of various inflammatory diseases.…”

Signal transduction and chemotaxis in mast cells

“…Similarly, SHIP1 knockout mice also exhibited mast cell hyperplasia, increased cytokine production and anaphylactic response (Haddon et al, 2009). A new small-molecule SHIP1 activator, AQX-1125, reduced cytokine production in splenocytes, inhibited the activation of mast cells and human leukocyte chemotaxis (Stenton et al, 2013b; Stenton et al, 2013a). However, the role of these phosphatases in mast cell chemotaxis remains to be determined.…”