R406, an Orally Available Spleen Tyrosine Kinase Inhibitor Blocks Fc Receptor Signaling and Reduces Immune Complex-Mediated Inflammation
Rigel Pharmaceuticals, South San Francisco, CA 94080, USA.Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 11/2006; 319(3):998-1008. DOI: 10.1124/jpet.106.109058
Recent compelling evidence has lead to renewed interest in the role of antibodies and immune complexes in the pathogenesis of several autoimmune disorders, such as rheumatoid arthritis. These immune complexes, consisting of autoantibodies to self-antigens, can mediate inflammatory responses largely through binding and activating the immunoglobulin Fc receptors (FcRs). Using cell-based structure activity relationships with cultured human mast cells, we have identified the small molecule R406 [N4-(2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine] as a potent inhibitor of immunoglobulin E (IgE)- and IgG-mediated activation of Fc receptor signaling (EC(50) for degranulation = 56-64 nM). Here we show that the primary target for R406 is the spleen tyrosine kinase (Syk), which plays a key role in the signaling of activating Fc receptors and the B-cell receptor (BCR). R406 inhibited phosphorylation of Syk substrate linker for activation of T cells in mast cells and B-cell linker protein/SLP65 in B cells. R406 bound to the ATP binding pocket of Syk and inhibited its kinase activity as an ATP-competitive inhibitor (K(i) = 30 nM). Furthermore, R406 blocked Syk-dependent FcR-mediated activation of monocytes/macrophages and neutrophils and BCR-mediated activation of B lymphocytes. R406 was selective as assessed using a large panel of Syk-independent cell-based assays representing both specific and general signaling pathways. Consistent with Syk inhibition, oral administration of R406 to mice reduced immune complex-mediated inflammation in a reverse-passive Arthus reaction and two antibody-induced arthritis models. Finally, we report a first-inhuman study showing that R406 is orally bioavailable, achieving exposures capable of inhibiting Syk-dependent IgE-mediated basophil activation. Collectively, the results show R406 potential for modulating Syk activity in human disease.
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- "In fact, several SYK inhibitors have been developed and some of them have entered clinical trials. These include fostamatinib, also called R-788 (Braselmann et al., 2006; Weinblatt et al., 2014) and PRT062607 (Simmons, 2013). Fostamanitib , an oral SYK inhibitor, has been successfully used in a phase II clinical trial for treatment of patients with rheumatoid arthritis (Weinblatt et al., 2010; Weinblatt et al., 2014). "
ABSTRACT: Mast cells play crucial roles in both innate and adaptive arms of the immune system. Along with basophils, mast cells are essential effector cells for allergic inflammation that causes asthma, allergic rhinitis, food allergy and atopic dermatitis. Mast cells are usually increased in inflammatory sites of allergy and, upon activation, release various chemical, lipid, peptide and protein mediators of allergic reactions. Since antigen/immunoglobulin E (IgE)-mediated activation of these cells is a central event to trigger allergic reactions, innumerable studies have been conducted on how these cells are activated through cross-linking of the high-affinity IgE receptor (FcεRI). Development of mature mast cells from their progenitor cells is under the influence of several growth factors, of which the stem cell factor (SCF) seems to be the most important. Therefore, how SCF induces mast cell development and activation via its receptor, KIT, has been studied extensively, including a cross-talk between KIT and FcεRI signaling pathways. Although our understanding of the signaling mechanisms of the FcεRI and KIT pathways is far from complete, pharmaceutical applications of the knowledge about these pathways are underway. This review will focus on recent progresses in FcεRI and KIT signaling and chemotaxis. Copyright © 2015. Published by Elsevier B.V.European journal of pharmacology 05/2015; DOI:10.1016/j.ejphar.2015.02.057 · 2.53 Impact Factor
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- "The relatively low rate of responses observed after dasatinib treatment when compared to kinase inhibitors targeting BTK, SYK, or PI3Kδ may be due to the fact that LYN functions in vivo as a negative regulator of BCR signaling (Hibbs et al., 1995; Nishizumi et al., 1995) (Table 1). Fostamatinib (FosD, R788) is an orally available inhibitor of SYK (Braselmann et al., 2006). In vitro, its bioactive form called R406 reduces CLL cell migration, chemokine secretion and BCR signaling (Quiroga et al., 2009). "
ABSTRACT: Chronic Lymphocytic Leukemia (CLL) is a prototype microenvironment-dependent B-cell malignancy, in which the neoplastic B cells co-evolve together with a supportive tissue microenvironment, which promotes leukemia cell survival, growth, and drug-resistance. Chemo-immunotherapy is an established treatment modality for CLL patients, resulting in high rates of responses and improved survival, especially in low-risk CLL. New, alternative treatments target B-cell receptor (BCR) signaling and the Chemokine (C-X-C motif) Receptor 4 (CXCR4)- Chemokine (C-X-C motif) Ligand 12 (CXCL12) axis, which are key pathways of CLL-microenvironment cross talk. The remarkable clinical efficacy of inhibitors targeting the BCR-associated kinases bruton’s tyrosine kinase (BTK) and phosphoinositide 3-kinase delta (PI3Kδ) challenge established therapeutic paradigms and corroborate the central role of BCR signaling in CLL pathogenesis. In this review, we discuss the cellular and molecular components of the CLL microenvironment. We also describe the emerging therapeutic options for CLL patients, with a focus on inhibitors of CXCR4-CXCL12 and BCR signaling.Pharmacology [?] Therapeutics 12/2014; 144(3). DOI:10.1016/j.pharmthera.2014.07.003 · 9.72 Impact Factor
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- "We thus wondered whether the detected BCR opening is associated with the Syk/ITAM signal amplification process we have described previously (Rolli et al., 2002) and that was recently confirmed by another study (Mukherjee et al., 2013). To test this, we pretreated splenic B cells with the Src-family kinase inhibitor PP2, or the Syk inhibitor R406, prior to their activation with Lat-A (Braselmann et al., 2006). While the PP2-treatment only delays the opening of the IgM-BCR oligomer, this process no longer occurs in the presence of the Syk inhibitor R406 (Figure 5A,B). "
ABSTRACT: Binding of antigen to the B cell antigen receptor (BCR) initiates a multitude of events resulting in B cell activation. How the BCR becomes signaling-competent upon antigen binding is still a matter of controversy. Using a high-resolution proximity ligation assay (PLA) to monitor the conformation of the BCR and its interactions with co-receptors at a 10–20 nm resolution, we provide direct evidence for the opening of BCR dimers during B cell activation. We also show that upon binding Syk opens the receptor by an inside-out signaling mechanism that amplifies BCR signaling. Furthermore, we found that on resting B cells, the coreceptor CD19 is in close proximity with the IgD-BCR and on activated B cells with the IgM-BCR, indicating nanoscale reorganization of receptor clusters during B cell activation. DOI: http://dx.doi.org/10.7554/eLife.02069.001eLife Sciences 06/2014; eLife 2014;3:e02069(3). DOI:10.7554/eLife.02069 · 9.32 Impact Factor
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