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

Abstract

BACKGROUNDThe SH2-containing inositol-5′-phosphatase 1 (SHIP1) metabolizes PI(3,4,5)P3 to PI(3,4)P2. SHIP1-deficient mice exhibit progressive inflammation. Pharmacological activation of SHIP1 is emerging as a potential therapy for pulmonary inflammatory diseases. Here we characterize the efficacy of AQX-1125, a small-molecule SHIP1 activator currently in clinical development. EXPERIMENTAL APPROACHThe effects of AQX-1125 were tested in several in vitro assays: on enzyme catalytic activity utilizing recombinant human SHIP1, on Akt phosphorylation in SHIP1-proficient and SHIP1-deficient cell lines, on cytokine release in murine splenocytes, on human leukocyte chemotaxis using modified Boyden chambers and on b-hexosaminidase release from murine mast cells. In addition, pharmacokinetic and drug distribution studies were performed in rats and dogs. RESULTSAQX-1125 increased the catalytic activity of human recombinant SHIP1, an effect, which was absent after deletion of the C2 region. AQX-1125 inhibited Akt phosphorylation in SHIP1-proficient but not in SHIP1-deficient cells, reduced cytokine production in splenocytes, inhibited the activation of mast cells and inhibited human leukocyte chemotaxis. In vivo, AQX-1125 exhibited >80% oral bioavailability and >5 h terminal half-life. CONCLUSIONSConsistent with the role of SHIP1 in cell activation and chemotaxis, the SHIP1 activator AQX-1125 inhibits Akt phosphorylation, inflammatory mediator production and leukocyte chemotaxis in vitro. The in vitro effects and the pharmacokinetic properties of the compound make it a suitable candidate for in vivo testing in various models of inflammation.

SHIP2: Structure, Function and Inhibition

“…Another SHIP1 activator, AQX‐1125 ( 32 ), is orally active and reduces the response to allergen challenge and to airway inflammation in asthma . Pharmacokinetic studies of AQX‐1125 in dogs and rats have been carried out, and the tissue distribution in rats has been analysed . At a concentration of 300 μ m it increases SHIP1 activity by 20 % and does so by decreasing K M and increasing k cat / K M .…”

“…Pharmacokinetic studies of AQX‐1125 in dogs and rats have been carried out, and the tissue distribution in rats has been analysed . At a concentration of 300 μ m it increases SHIP1 activity by 20 % and does so by decreasing K M and increasing k cat / K M . Another compound, AQX‐MN115 ( 33 ), under the same conditions increases SHIP1 activity by 77 % and does so by having similar effects on the kinetic parameters …”

Current Pharmacologic Approaches in Painful Bladder Research: An Update

“…AQX-1125 represents a new pharmaceutical class of compounds [ 26 ], activators of SH2-containing inositol-5´-phosphatase 1 (SHIP1). SHIP1 is an intracellular protein whose expression is primarily restricted to cells of the haematopoietic lineage.…”

“…Activation of SHIP1 has an anti-inflammatory effect [ 29 ]. The highly restricted expression pattern of SHIP1 in addition to its ability to act as a negative regulator of immune cell signalling makes it a highly attractive target for the development of anti-inflammatory therapeutics, and pharmacological activation of SHIP1 has emerged as a novel approach for the therapy of various inflammatory diseases [ 26 , 29 , 30 ].…”

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.…”