Selected Publications

Aquinox Scientific Presentations

 

Chemical Activation of the SHIP1 Inositol Lipid Phosphatase: A Novel Therapeutic Strategy to Suppress B-cell Receptor Signaling and CXCR4 Expression in Malignant Human B Cells

58th Annual American Society of Hematology Meeting
Dec 3-16, 2016
Graham Packham, Beatriz Valle-Argos, Elizabeth Lemm, Lindsay D Smith, Nicola J Weston-Bell, Yohannes Gebreselassie, Andrew J Steele, Freda K Stevenson, Mark S Cragg, Francesco Forconi, Jennifer Cross, Curtis Harwig and Lloyd Mackenzie

Click here to view poster.

SHIP-1 Activation Provides Significant Benefit in Interstitial Cystitis/Bladder Pain Syndrome: Results of a Phase 2 Randomized Placebo Controlled Trial 

111th American Urological Association (AUA) Annual Meeting
May 6-10, 2016
J. Curtis Nickel, B. Egerdie, E. Davis, R. Evans, H. Biagi, S. Shrewsbury
Click here to view poster.

Plasma and Urinary Pharmacokinetics of the a Novel, Oral SHIP1 Activator, AQX-1125 in Female Patients with Interstitial Cystitis

111th American Urological Association (AUA) Annual Meeting
May 6-10, 2016
J. Curtis Nickel, R. Evans, P. Tam, J. Toews, L. F. Mackenzie, H. Biagi, S. Shrewsbury
Click here to view poster.

Effect of AQX-1125 on Urinary Bladder Inflammation and Pain Induced by Cyclophosphamide in Rats, by Targeting the SHIP1 Pathway

111th American Urological Association (AUA) Annual Meeting
May 6-10, 2016
J. L. Cross, C. Harwig, P. Tam, J. Toews and L. F. Mackenzie,
Click here to view poster.

Plasma and Urinary Pharmacokinetics of the Novel, Oral SHIP1 Activator, AQX-1125 in Interstitial Cystitis/ Bladder Pain Syndrome (IC/BPS) –Results of the Phase 2 LEADERSHIP Trial

31st Annual European Association of Urology Congress
March 11-15, 2016
J. Curtis Nickel, R. Evans, P. Tam, J. Toews, L. Mackenzie, H. Biagi, S. Shrewsbury
Click here to view poster.

  Safety and Efficacy of AQX-1125 in Interstitial Cystitis/Bladder Pain Syndrome - Results of the Phase 2 LEADERSHIP Trial

International Society for the Study of BPS (ESSIC) Annual Meeting 2015 - Rome, IT
September 17-19, 2015
J. Curtis Nickel, Kingston, Canada; Edward Davis, Glendora, CA, US; Pat Tam, Lloyd Mackenzie, Heidi Biagi, Stephen Shrewsbury, Vancouver, Canada
Click here to view abstract.

AQX-1125, a Small Molecule SHIP1 Activator, is Effective in a Murine NASH Model

Keystone Symposia’s 2015 conference on: Liver Metabolism and Nonalcoholic Fatty Liver Disease (NAFLD) - Whistler, BC
March 23, 2015
J.L. Cross, C. Harwig, P. Tam, J. Toews and L.F. Mackenzie
Click here to view poster.

The FLAGSHIP Study: A 12-week Phase II Study to Evaluate the Efficacy and Safety of AQX-1125 Following Exacerbations in Patients with Chronic Obstructive Pulmonary Disease (COPD) by Targeting the SHIP1 Pathway

American Thoracic Society 2014 - San Diego, CA
May 16-21, 2014
Bjermer. L, Vestbo. J, Kuna. P, Saarelainen. P, Balint. B, Kalia. V, Tam. P, Mackenzie. L, Shrewsbury. S
Click here to view poster.

Effect of AQX-1125 on Urinary Bladder Inflammation and Pain Induced by Cyclophosphamide in Rats, by Targeting the SHIP1 Pathway

Click here to view poster.

The Effect Of AQX-1125, A Selective Oral SHIP1 Activator, On Lipoplysaccharide-Induced Cellular and Biochemical Changes in Sputum From Healthy Volunteers

American Thoracic Society 2013 - Philadelphia, PA
May 7-22, 2013
J. S. Elborn, S.P. Smith, V. Brown, D. Chernoff, P. Tam, J. Neville, J. Toews, G.R. Stenton, C. Harwig, T. MacRury, L.F. Mackenzie
Click here to view poster.

The Effects Of The Novel SHIP1 Activator AQX-1125 On Allergen-Induced Responses In Mild To Moderate Asthma

American Thoracic Society 2013 - Philadelphia, PA
May 7-22, 2013
B.R. Leaker, B.R. O’Connor, P.J. Barnes, D. Chernoff, P. Tam,  J. Neville, J. Toews, G.R. Stenton, C. Harwig, T. MacRury, and L.F. Mackenzie. 
Click here to view poster.

Prophylactic or Therapeutic AQX-1125, a Small Molecule SHIP1 Activator, Inhibits Bleomycin-Induced Pulmonary Fibrosis in Mice

American Thoracic Society 2013 - Philadelphia, PA
May 7-22, 2013
L.F. Mackenzie, G.R. Stenton,  E. Esposito, S. Cuzzocrea, C. Szabo, T. MacRury. 
Click here to view poster.

AQX-1125, a SHIP1 Activator, In Clinical Development For Pulmonary Inflammation: Pharmacokinetics, Metabolism And Tolerability In Healthy Human Volunteers

American Thoracic Society 2012 - San Francisco, USA 
P. Tam, L.F. Mackenzie, J. Toews, G.R. Stenton, C. Harwig, J. Raymond, C. Szabo, T. MacRury, D. Chernoff (2012) AQX-1125, A SHIP1 Activator In Clinical Development For Pulmonary Inflammation: Pharmacokinetics, Metabolism And Tolerability In Healthy Humans Volunteers. Am J Respir Crit Care Med 185;2012:A2754
May 18–23, 2012
Click here to view poster.

AQX-1125, a SHIP1 Activator, Inhibits Chemotaxis In Vitro and Exerts Pleiotropic Anti-Inflammatory Effects in a Rodent Model of Endotoxin-Induced Pulmonary Inflammation

American Thoracic Society 2012 - San Francisco, USA
G.R. Stenton, J.L. Cross, L.F. Mackenzie, J. Wu, N. Ogden, J. Toews, C. Harwig, J. Raymond, T. MacRury, C. Szabo (2012) AQX-1125, A SHIP1 Activator, Inhibits Chemotaxis In Vitro And Exerts Pleiotropic Anti-Inflammatory Effects In A Rodent Model Of Endotoxin-Induced Pulmonary Inflammation. Am J Respir Crit Care Med 185;2012:A3696
May 18–23, 2012
Click here to view poster.

An Emerging, Novel Modulator - SHIP1, a Phosphatidylinositide Phosphatase: From Basic Science to Therapeutic Applications

Ninth International Discovery on Target Conference - Boston, MA
November 2–4, 2011
Click here to view poster.

AQX-1125, A First-in-Class Clinical-Stage SHIP1 Activator Small Molecule for the Treatment of Pulmonary Diseases: Supression of Chemotaxis in vitro and Efficacy in Rodent Models of Asthma and COPD in vivo

Tenth World Congress on Inflammation - Paris, FRA
June 25–29, 2011
Szabo, C., Mackenzie, L.F., Stenton, G.R., Tam, P., Cross, J.L., Harwig, C., Raymond, J., Toews, J., Chernoff, D., and MacRury, T. (2011) AQX-1125, a first-in-class clinical-stage SHIP1 activator small  molecule for the treatment of pulmonary diseases: suppression of chemotaxis in vitro and efficacy in rodent models of asthma and COPD in vivo. Inflam Res 60, S231.
Click here to view poster.

AQX-1125, A Modulator of the SHIP1/PI3K Pathway, Suppresses Chemotaxis and Inflammation

2011 American Academy of Allergy, Asthma, and Immunology Annual Meeting - San Francisco, CA
March 18–22, 2011
Cross, J.L., Stenton, G.R., Roberts, H., and Mackenzie, L.F. (2011). AQX-1125 a modulator of the SHIP1/PI3K Pathway, suppresses chemotaxis and inflammation. J Allergy Clin Immunol 127, AB65.
Click here to view poster.

AQX-1125, A Modulator of the SHIP1/PI3K Pathway, Suppresses Chemotaxis and Inflammation

Keystone Symposia on Molecular and Cellular Biology - Keystone, CO
February 13–18, 2011
Click here to view poster.

Selected Papers on AQX-1125

Leaker BR1, Barnes PJ, O'Connor BJ, Ali FY, Tam P, Neville J, Mackenzie LF, MacRury T. (2014). The effects of the novel SHIP1 activator AQX-1125 on allergen-induced responses in mild to moderate asthma. Clin Exp Allergy. 2014 Sep 44(9):1146-53.

Stenton, G. R., Mackenzie, L. F., Tam, P., Cross, J. L., Harwig, C., Raymond, J., Toews, J., Wu, J., Ogden, N., MacRury, T., Szabo, C. (2013). Characterization of AQX-1125, a small-molecule SHIP1 activator: Part 1. Effects on inflammatory cell activation and chemotaxis in vitro and pharmacokinetic characterization in vivo. Br J Pharmacol 168(6): 1506-18.

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. Br J Pharmacol 168(6): 1519-29. 

Reviews on SHIP1

Rauh, M. J., Sly, L. M., Kalesnikoff, J., Hughes, M. R., Cao, L. P., Lam, V., and Krystal, G. (2004). The role of SHIP1 in macrophage programming and activation. Biochem Soc Trans 32, 785-788.

March, M. E., and Ravichandran, K. (2002). Regulation of the immune response by SHIP. Semin Immunol 14, 37-47.

Kalesnikoff, J., Lam, V., and Krystal, G. (2002). SHIP represses mast cell activation and reveals that IgE alone triggers signaling pathways which enhance normal mast cell survival. Mol Immunol 38, 1201-1206.

Krystal, G. (2000). Lipid phosphatases in the immune system. Semin Immunol 12(4): 397-403.

Selected Papers on SHIP1

Haddon, D. J., F. Antignano, et al. (2009). SHIP1 Is a repressor of mast cell hyperplasia, cytokine production, and allergic inflammation in vivo. J Immunol 183(1): 228-36.

Helgason, C. D., Damen, J. E., Rosten, P., Grewal, R., Sorensen, P., Chappel, S. M., Borowski, A., Jirik, F., Krystal, G., and Humphries, R. K. (1998). Targeted disruption of SHIP leads to hemopoietic perturbations, lung pathology, and a shortened life span. Genes Dev 12, 1610-1620.

Rauh, M. J., Ho, V., Pereira, C., Sham, A., Sly, L. M., Lam, V., Huxham, L., Minchinton, A. I., Mui, A., and Krystal, G. (2005). SHIP represses the generation of alternatively activated macrophages. Immunity 23, 361-374.

Sly, L. M., Rauh, M. J., Kalesnikoff, J., Song, C. H., and Krystal, G. (2004). LPS-induced upregulation of SHIP is essential for endotoxin tolerance. Immunity 21, 227-239.

Huber, M., Helgason, C. D., Damen, J. E., Liu, L., Humphries, R. K., and Krystal, G. (1998). The src homology 2-containing inositol phosphatase (SHIP) is the gatekeeper of mast cell degranulation. Proc Natl Acad Sci USA 95, 11330-11335.

Ong, C. J., Ming-Lum, A., Nodwell, M., Ghanipour, A., Yang, L., Williams, D. E., Kim, J., Demirjian, L., Qasimi, P., Ruschmann, J., Cao, L., Ma, K., Chung, S. W., Duronio, V., Andersen, R. J., Krystal, G., and Mui, A. (2007). Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells. Blood 110(6), 1942-1949.

Ganesan, L. P., T. Joshi, et al. (2006). FcgammaR-induced production of superoxide and inflammatory cytokines is differentially regulated by SHIP through its influence on PI3K and/or Ras/Erk pathways. Blood 108(2): 718-25.

Kalesnikoff, J., N. Baur, et al. (2002). SHIP negatively regulates IgE + antigen-induced IL-6 production in mast cells by inhibiting NF-kappa B activity. J Immunol 168(9): 4737-46.

Kamata, T., M. Yamashita, et al. (2003). src homology 2 domain-containing tyrosine phosphatase SHP-1 controls the development of allergic airway inflammation. J Clin Invest 111(1): 109-19.

Liu, Q., F. Shalaby, et al. (1998). The SH2-containing inositol polyphosphate 5-phosphatase, ship, is expressed during hematopoiesis and spermatogenesis. Blood 91(8): 2753-9.

Oh, S. Y., T. Zheng, et al. (2007). Src homology 2 domain-containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung. J Allergy Clin Immunol 119(1): 123-31.

Ooms, L. M., K. A. Horan, et al. (2009). The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease. Biochem J 419(1): 29-49.

Vonakis, B. M., S. Gibbons, Jr., et al. (2001). Src homology 2 domain-containing inositol 5' phosphatase is negatively associated with histamine release to human recombinant histamine-releasing factor in human basophils. J Allergy Clin Immunol 108(5): 822-31.

Stenton GR, Mackenzie LF, Tam P, Cross JL, Harwig C, Raymond J, Toews J, Wu J, Ogden N, MacRury T, Szabo C. Characterization of AQX-1125, a small-molecule SHIP1 activator Part 1. Effects on inflammatory cell activation and chemotaxis in vitro and pharmacokinetic characterization in vivo.

Stenton GR, Mackenzie LF, Tam P, Cross JL, Harwig C, Raymond J, Toews J, Chernoff D, MacRury T, Szabo C.  Characterization of AQX-1125, a small-molecule SHIP1 activator Part 2. Efficacy studies in allergic and pulmonary inflammation models in vivo.

Chemistry Papers on Aquinox Compounds and Analogues

Yang, L., Williams, D. E., Mui, A., Ong, C., Krystal, G., van Soest, R., and Andersen, R. J. (2005). Synthesis of pelorol and analogues: activators of the inositol 5-phosphatase SHIP. Org Lett 7, 1073-1076.

Reviews on the PI3K Pathway and Cancer Drug Discovery

Harris, S. J., Parry, R.V., Westwick, J., and Ward, S. G. (2008). Phosphoinositide Lipid Phosphatases: Natural Regulators of Phosphoinositide 3-Kinase Signaling in T Lymphocytes. J Bio Chem 283(5), 2465-2469.

Crabbe, T., Welham, M. J., and Ward, S. G. (2007). The PI3K inhibitor arsenal: choose your weapon! Trends Biochem Sci 32(10), 450-456.

Hennessy, B. T., Smith, D. L., Ram, P. T., Lu, Y., and Mills, G. B. (2005). Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4, 988-1004.

Cully, M., You, H., Levine, A. J., and Mak, T. W. (2006). Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 6, 184-192.

Firestein, G. S. (2006). Inhibiting inflammation in rheumatoid arthritis. N Engl J Med 354(1): 80-2.

Ruckle, T., M. K. Schwarz, et al. (2006). PI3Kgamma inhibition: towards an 'aspirin of the 21st century'? Nat Rev Drug Discov 5(11): 903-18.

Selected Papers on PI3K

Ali, K., M. Camps, et al. (2008). Isoform-specific functions of phosphoinositide 3-kinases: p110 delta but not p110 gamma promotes optimal allergic responses in vivo. J Immunol 180(4): 2538-44.

Ito, K., G. Caramori, et al. (2007). Therapeutic potential of phosphatidylinositol 3-kinase inhibitors in inflammatory respiratory disease. J Pharmacol Exp Ther 321(1): 1-8.

Lee, K. S., H. K. Lee, et al. (2006). Inhibition of phosphoinositide 3-kinase delta attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model. FASEB J 20(3): 455-65. 

Selected Papers on Chronic Obstructive Pulmonary Disease (COPD)

Hurst, J.R., Donaldson, G.C., Quint, J.K., Goldring, J.J., Baghai-Ravary, R., Wedzicha, J.A. (2009). Temporal clustering of exacerbations in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 179(5): 369-374.

Aaron, S.D. (2009). COPD exacerbations: predicting the future from the recent past. Am J Respir Crit Care Med 179(5): 335-336.

Sethi, S., Mahler, D.A., Marcus, P., Owen, C.A., Yawn, B., Rennard, S. (2012). Inflammation in COPD: implications for management. Am J Med 125(12): 1162-1170.

Leidy, N.K., Wilcox, T.K., Jones, P.W., Murray, L., Winnette, R., Howard, K., Petrillo, J., Powers, J., Sethi, S.; EXACT-PRO Study Group. (2010). Development of the EXAcerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT): a patient-reported outcome (PRO) measure. Value Health 13(8): 965-975.

Leidy, N.K., Wilcox, T.K., Jones, P.W., Roberts, L., Powers, J.H., Sethi, S.; EXACT-PRO Study Group. (2011). Standardizing measurement of chronic obstructive pulmonary disease exacerbations. Reliability and validity of a patient-reported diary. Am J Respir Crit Care Med 183(3): 323-329.

Selected Papers on Bladder Pain Syndrome (BPS)/Interstitial Cystitis (IC)

Hanno, P., Lin, A., Nordling, J., Nyberg, L., van Ophoven, A., Ueda, T., Wein, A.; Bladder Pain Syndrome Committee of the International Consultation on Incontinence. (2010). Bladder Pain Syndrome Committee of the International Consultation on Incontinence. Neurourol Urodyn 29(1): 191-198.

Humphrey, L., Arbuckle, R., Moldwin, R., Nordling, J., van de Merwe, J.P., Meunier, J., Crook, T., Abraham, L. (2012). Eur Urol 61(2): 271-279.