A5101726803- Protein Tyrosine Phosphatases
- Immunotherapy and Immune Responses
- Systemic Lupus Erythematosus Research
- PI3K/AKT/mTOR signaling in cancer
- T-cell and B-cell Immunology
- Glycosylation and Glycoproteins Research
- Immune Cell Function and Interaction
- Endoplasmic Reticulum Stress and Disease
- Galectins and Cancer Biology
- Liver Diseases and Immunity
- Chronic Lymphocytic Leukemia Research
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Cytokine Signaling Pathways and Interactions
- Cytomegalovirus and herpesvirus research
- Immune Response and Inflammation
- Renal Transplantation Outcomes and Treatments
- Pregnancy and Medication Impact
- Asthma and respiratory diseases
- Monoclonal and Polyclonal Antibodies Research
- Pharmacological Effects and Toxicity Studies
- Chronic Kidney Disease and Diabetes
- Wnt/β-catenin signaling in development and cancer
- Cell Adhesion Molecules Research
- Diabetes and associated disorders
- Protein Kinase Regulation and GTPase Signaling
Aurinia (Canada)
2021-2024
Kineta (United States)
2021
Inimex Pharmaceuticals (Canada)
2011-2019
University of British Columbia
2003-2015
The 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 AQX-1125, small-molecule activator currently in clinical development.The effects AQX-1125 were tested several vitro assays: on enzyme catalytic activity utilizing recombinant human SHIP1, Akt phosphorylation...
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 inflammation. Experimental Approach ‐1125 was administered orally mouse model passive cutaneous anaphylaxis PCA number respiratory inflammation including: cigarette smoke, LPS ovalbumin OVA )‐mediated airway dependency the mechanism action by comparing wild‐type SHIP1‐deficient mice subjected to an...
Calcineurin inhibitors (CNIs) affect kidney electrolyte handling and blood pressure (BP) through an effect on the distal tubule. The second-generation CNI voclosporin causes hypomagnesaemia hypercalciuria less often than tacrolimus. This suggests different effects tubule, but this has not yet been investigated experimentally.
Abstract CD45 is a leukocyte-specific protein tyrosine phosphatase and an important regulator of AgR signaling in lymphocytes. However, its function other leukocytes not well-understood. In this study, we examine the dendritic cells (DCs). Analysis DCs from CD45-positive CD45-null mice revealed that required for development but does influence DC maturation induced by TLR agonists. affected phosphorylation state Lyn, Hck, Fyn bone marrow-derived dysregulated LPS-induced Lyn activation....
The phosphatase SHIP1 negatively regulates the PI3K pathway, and its predominant expression within cells of haematopoietic compartment makes activation a novel strategy to limit inflammatory signalling generated through PI3K. AQX-1125 is only clinical-stage, orally administered, activator. Here, we demonstrate prophylactic therapeutic effects AQX-1125, in mouse model bleomycin-induced lung fibrosis.
Kidney transplant recipients (KTRs) are at increased risk for a more severe course of COVID-19, due to their pre-existing comorbidity and immunosuppression. Consensus protocols recommend lowering immunosuppression in KTRs with acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the optimal combination remains unclear. Calcineurin inhibitors (CNIs) cornerstone immunosuppressants used some have been reported possess antiviral activity against RNA viruses, including...
PI3K signaling is a common feature of B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and diffuse large lymphoma (DLBCL), inhibitors have been introduced into the clinic. However, there remains clear need to develop new strategies target signaling. activity countered by Src homology domain 2-containing inositol-5'-phosphatase 1 (SHIP1) and, here, we characterized novel SHIP1 activator, AQX-435, in preclinical models malignancies.
CD45 is a transmembrane, two-domain protein-tyrosine phosphatase expressed exclusively in nucleated hematopoietic cells. The Src family kinase, Lck, major substrate T cells and dephosphorylation of Lck important for both cell development activation. However, how the specificity phosphatases such as achieved not well understood. Analysis interaction between cytoplasmic domain its substrate, revealed that active, membrane-proximal (CD45-D1) bound to phosphorylated kinase domain, SH2 unique...
Abstract H2-M3-restricted CD8+ T cells provide early protection against bacterial infections. In this study, we demonstrate that activated signals for efficient CD4+ cell priming. C57BL/6 mice immunized with dendritic coated the MHC class II-restricted listeriolysin O peptide LLO190–201 (LLO) generated capable of responding to Listeria monocytogenes (LM) infection. Inclusion a formylated fMIGWII (fMIG), but not Ia-restricted peptides, during immunization LLO significantly increased...
Lupus nephritis (LN) is a major cause of morbidity and mortality with lifetime incidence up to 60% in systemic lupus erythematosus (SLE).1 Cardiovascular diseases (CVD) are also the leading death patients SLE.2 LN an independent risk factor for CVD which increases by two times as compared SLE without LN.3 Goals treatment include preserving kidney function reducing mortality, while minimizing related adverse events improving quality life.
Abstract Signaling via the B-cell receptor (BCR) is a major driver of malignant proliferation and survival in malignancies including chronic lymphocytic leukemia (CLL). The role kinases BCR signalling well understood kinase inhibitors are effective therapies for cancers. However, resistance increasingly common new drugs required. In this study we investigated an alternate strategy to block signaling small molecule activation SHIP1, inositol lipid phosphatase which suppresses PI3...
Abstract Background and Aims The calcineurin inhibitors (CNI) cyclosporine (CSA) tacrolimus (TAC) were revolutionary immunosuppressants when first introduced for solid organ transplantation in the 1980s. Voclosporin (VCS), a novel CNI, recently became oral therapy approved United States, Great Britain, Europe treatment of active lupus nephritis based on positive results from Phase 2 3 clinical trials. Unlike CSA TAC, VCS has demonstrated consistent pharmacokinetic pharmacodynamic profile,...
Abstract Background and Aims Clinically, the calcineurin inhibitor tacrolimus frequently causes hypercalciuria hypomagnesemia by inhibiting kidney tubular calcium magnesium reabsorption. Voclosporin, a novel approved in USA Europe for treatment of adults with active lupus nephritis, has fewer side-effects including less hypomagnesemia. However, differences between effects voclosporin are unknown. To address this, we compared tacrolimus, voclosporin, vehicle rats. Method Tacrolimus (0.5...
1Microbiology And Immunology, University of British Columbia, Vancouver/British Columbia/CANADA, 2Microbiology Vancouver/BC/CANADA
Rationale: Pharmacological modulation of the phosphoinositide 3-kinase (PI3K)/Akt pathway is an established approach to controlling inflammatory disorders. SH2containing inositol-5'-phosphatase 1 (SHIP1) metabolizes PI(3,4,5)P3 PI(3,4)P2. SHIP1-deficient mice exhibit pulmonary inflammation, characterized by significant granulocyte recruitment into lung. Preclinical pharmacological activation SHIP1 small molecule AQX-1125, reported herein as emerging innovative therapy for diseases.