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Syk inhibitor

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https://www.readbyqxmd.com/read/29781506/articular-cartilage-protection-in-ctsk-mice-is-associated-with-cellular-and-molecular-changes-in-subchondral-bone-and-cartilage-matrix
#1
Fabiana N Soki, Ryu Yoshida, David N Paglia, Le T Duong, Marc F Hansen, Hicham Drissi
Osteoarthritis (OA) is a degenerative disease and a major cause of chronic disability in aging individuals. Cathepsin K (CatK), encoded by the Ctsk gene, has been implicated in the pathogenesis of pycnodysostosis and osteoporosis. The use of a selective inhibitor of CatK was recently shown to delay OA progression in rabbits. However, the cellular mechanisms underlying these protective effects remain unexplored. We examined articular cartilage maintenance and joint bone remodeling using Ctsk null mice (Ctsk-/- ) which underwent destabilization of the medial meniscus (DMM)...
May 21, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29781323/targeting-the-b-cell-receptor-pathway-a-review-of-current-and-future-therapies-for-non-hodgkin-s-lymphoma
#2
Thomas D Rodgers, Patrick M Reagan
The B-cell receptor (BCR) pathway is a crucial aspect of mature lymphocytes and is maintained in B-cell neoplasms. Many small module inhibitors targeting kinases within the BCR pathway are approved, with others in development, offering alternative treatment options to standard chemoimmunotherapy. Areas Covered: This review covers both approved inhibitors and investigational inhibitors of spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), and phosphoinositide-3-kinase (PI3K) in the treatment of B-cell lymphomas...
May 20, 2018: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/29763550/selective-inhibition-of-the-myeloid-src-family-kinase-fgr-potently-suppresses-aml-cell-growth-in-vitro-and-in-vivo
#3
Mark C Weir, Sherry T Shu, Ravi K Patel, Sabine Hellwig, Li Chen, Li Tan, Nathanael S Gray, Thomas E Smithgall
Acute myelogenous leukemia (AML) is the most common hematologic malignancy in adults, and is often associated with constitutive tyrosine kinase signaling. These pathways involve the non-receptor tyrosine kinases Fes, Syk and the three Src-family kinases expressed in myeloid cells (Fgr, Hck, and Lyn). In this study, we report remarkable anti-AML efficacy of an N-phenylbenzamide kinase inhibitor, TL02-59. This compound potently suppressed the proliferation of bone marrow samples from twenty of twenty-six AML patients, with a striking correlation between inhibitor sensitivity and expression levels of the myeloid Src family kinases Fgr, Hck, and Lyn...
May 15, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29748439/autologous-t-cell-activation-fosters-abt-199-resistance-in-chronic-lymphocytic-leukemia-rationale-for-a-combined-therapy-with-syk-inhibitors-and-anti-cd20-moabs
#4
Esteban Enrique Elías, María Belén Almejún, Ana Colado, Gregorio Cordini, Maricef Vergara-Rubio, Enrique Podaza, Denise Risnik, María Cabrejo, Horacio Fernández-Grecco, Raimundo Fernando Bezares, María Del Rosario Custidiano, Julio César Sánchez-Ávalos, Ángeles Vicente, Gonzalo Martín Garate, Mercedes Borge, Mirta Giordano, Romina Gamberale
No abstract text is available yet for this article.
May 10, 2018: Haematologica
https://www.readbyqxmd.com/read/29728446/tas05567-a-novel-potent-and-selective-spleen-tyrosine-kinase-inhibitor-abrogates-immunoglobulin-mediated-autoimmune-and-allergic-reactions-in-rodent-models
#5
Hiroaki Hayashi, Ryusuke Kaneko, Shunsuke Demizu, Daichi Akasaka, Manabu Tayama, Takafumi Harada, Hiroki Irie, Yoshio Ogino, Naoko Fujino, Eiji Sasaki
Spleen tyrosine kinase (Syk) is involved in regulation of B-cell receptor (BCR) and Fc receptor (FcR) downstream signal pathways. Syk plays an essential role in production of inflammatory mediators and differentiation in various immune cells and is therefore an attractive target for treating inflammatory conditions, such as autoimmune and allergic diseases. We identified TAS05567 as a highly selective Syk inhibitor and evaluated its therapeutic potential in animal models. In vitro biochemical assays were performed with available kinase assay panels...
May 4, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29721381/foxo1-promotes-resistance-of-non-hodgkin-lymphomas-to-anti-cd20-based-therapy
#6
Beata Pyrzynska, Michal Dwojak, Abdessamad Zerrouqi, Giulia Morlino, Piotr Zapala, Nina Miazek, Agnieszka Zagozdzon, Kamil Bojarczuk, Malgorzata Bobrowicz, Marta Siernicka, Marcin M Machnicki, Stefania Gobessi, Joanna Barankiewicz, Ewa Lech-Maranda, Dimitar G Efremov, Przemyslaw Juszczynski, Dinis Calado, Jakub Golab, Magdalena Winiarska
Diminished overall survival rate of non-Hodgkin lymphoma (NHL) patients treated with a combination regimen of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) has been recently linked to recurrent somatic mutations activating FOXO1. Despite of the clinical relevance of this finding, the molecular mechanism driving resistance to R-CHOP therapy remains largely unknown. Herein, we investigated the potential role of FOXO1 in the therapeutic efficacy of rituximab, the only targeted therapy included in the R-CHOP regimen...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29719615/identification-of-spleen-tyrosine-kinase-as-a-potential-therapeutic-target-for-esophageal-squamous-cell-carcinoma-using-reverse-phase-protein-arrays
#7
Mustafa A Barbhuiya, Manoj K Kashyap, Vinuth N Puttamallesh, Rekha Vijay Kumar, Xinyan Wu, Akhilesh Pandey, Harsha Gowda
The vast majority of esophageal cancers in China, India and Iran are esophageal squamous cell carcinomas (ESCC). A timely diagnosis provides surgical removal as the main therapeutic option for patients with ESCC. Currently, there are no targeted therapies available for ESCC. We carried out reverse phase protein array-based protein expression profiling of seven ESCC-derivedcell lines and a non-neoplastic esophageal epithelial cell line (Het-1A) to identify differentially expressed proteins in ESCC. SYK non-receptortyrosine kinase was overexpressed in six out of seven ESCC cell lines that were used in the study...
April 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29696684/fostamatinib-for-the-treatment-of-adult-persistent-and-chronic-immune-thrombocytopenia-results-of-two-phase-3-randomized-placebo-controlled-trials
#8
James Bussel, Donald M Arnold, Elliot Grossbard, Jiří Mayer, Jacek Treliński, Wojciech Homenda, Andrzej Hellmann, Jerzy Windyga, Liliya Sivcheva, Alhossain A Khalafallah, Francesco Zaja, Nichola Cooper, Vadim Markovtsov, Hany Zayed, Anne-Marie Duliege
Spleen tyrosine kinase (Syk) signaling is central to phagocytosis-based, antibody-mediated platelet destruction in adults with immune thrombocytopenia (ITP). Fostamatinib, an oral Syk inhibitor, produced sustained on-treatment responses in a phase 2 ITP study. In two parallel, phase 3, multicenter, randomized, double-blind, placebo-controlled trials (FIT1 and FIT2), patients with persistent/chronic ITP were randomized 2:1 to fostamatinib (n=101) or placebo (n=49) at 100mg BID for 24 weeks with a dose increase in non-responders to 150mg BID after 4 weeks...
April 26, 2018: American Journal of Hematology
https://www.readbyqxmd.com/read/29673901/the-role-of-syk-in-peripheral-t-cells
#9
Jeoung-Eun Park, Sirshendu Majumdar, David D Brand, Edward F Rosloniec, Ae-Kyung Yi, John M Stuart, Andrew H Kang, Linda K Myers
The aim of this study was to understand how Syk affects peripheral T cell function. T cells from Syk-/- chimeric mice and DR1 Sykfl/fl CD4cre conditional mice gave strong CD3-induced Th1, Th2, and Th17 cytokine responses. However, an altered peptide ligand (APL) of human CII (256-276) with two substitutions (F263N, E266D), also called A12, elicited only Th2 cytokine responses from Sykfl/fl T cells but not Sykfl/fl- CD4cre T cells. Western blots revealed a marked increase in the phosphorylation of Syk, JNK and p38 upon A12/DR1 activation in WT or Sykfl/fl T cells but not in Sykfl/fl CD4-cre cells...
April 16, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/29669391/translational-biomarkers-and-ex-vivo-models-of-joint-tissues-as-a-tool-for-drug-development-in-rheumatoid-arthritis
#10
Cecilie F Kjelgaard-Petersen, Adam Platt, Martin Braddock, Martin A Jenkins, Kishwar Musa, Emma Graham, Thorbjørn Gantzel, Gillian Slynn, Michael E Weinblatt, Morten A Karsdal, Christian S Thudium, Anne-C Bay-Jensen
OBJECTIVE: Rheumatoid arthritis (RA) is a chronic, autoimmune and degenerative joint disease leading to disability, reduced life quality, and increased mortality. Although several synthetic and biological disease modifying anti-rheumatic drugs (DMARDs) are available, there is still a medical need for novel drugs controlling disease progression. As only 10% of RA drug candidates that enter phase I trials are eventually FDA registered, there is an immediate requirement for translational drug development tools to facilitate early drug development decision making...
April 18, 2018: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/29669390/editorial-title-lessons-learned-from-a-failed-clinical-trial
#11
EDITORIAL
E F A Leijten, T R D J Radstake, K A Reedquist
Spleen tyrosine kinase (Syk), through its capacity to promote the pathogenic activation of B lymphocytes, myeloid cells, osteoclasts, and stromal fibroblast-like synoviocytes, has been subject to intense translational and clinical scrutiny as a potential therapeutic target in rheumatoid arthritis (RA) (1). Initial phase II clinical trials with the Syk inhibitor fostamatinib showed promising effectivity in treating RA patients that had displayed inadequate responses to methotrexate (2,3). However, concerns were raised of drug-dependent adverse effects in these studies, and fostamatinib did not improve disease in RA patients failing other biologic agents (4)...
April 18, 2018: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/29669173/second-generation-syk-inhibitor-entospletinib-ameliorates-fully-established-inflammation-and-bone-destruction-in-the-cherubism-mouse-model
#12
Tetsuya Yoshimoto, Tatsuhide Hayashi, Toshio Kondo, Mizuho Kittaka, Ernst J Reichenberger, Yasuyoshi Ueki
Cherubism is a craniofacial disorder characterized by maxillary and mandibular bone destruction. Gain-of-function mutations in the SH3-domain binding protein 2 (SH3BP2) are responsible for the excessive bone resorption caused by fibrous inflammatory lesions. A homozygous knock-in (KI) mouse model for cherubism (Sh3bp2KI/KI ) develops autoinflammation resulting in systemic bone destruction. While administration of the TNF-α blocker etanercept to neonatal Sh3bp2KI/KI mice prevented the disease onset, this therapy was not effective for adult Sh3bp2KI/KI mice or human cherubism patients who already had lesions...
April 18, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/29643476/inhibition-of-ovarian-tumor-cell-invasiveness-by-targeting-syk-in-the-tyrosine-kinase-signaling-pathway
#13
Yu Yu, Yohan Suryo Rahmanto, Meng-Horng Lee, Pei-Hsun Wu, Jude M Phillip, Chuan-Hsiang Huang, Michele I Vitolo, Stephanie Gaillard, Stuart S Martin, Denis Wirtz, Ie-Ming Shih, Tian-Li Wang
Cell motility and invasiveness are prerequisites for dissemination, and largely account for cancer mortality. We have identified an actionable kinase, spleen tyrosine kinase (SYK), which is keenly tightly associated with tumor progression in ovarian cancer. Here, we report that active recombinant SYK directly phosphorylates cortactin and cofilin, which are critically involved in assembly and dynamics of actin filament through phosphorylation signaling. Enhancing SYK activity by inducing expression of a constitutively active SYK mutant, SYK130E , increased growth factor-stimulated migration and invasion of ovarian cancer cells, which was abrogated by cortactin knockdown...
April 11, 2018: Oncogene
https://www.readbyqxmd.com/read/29625466/narrow-spectrum-kinase-inhibitors-demonstrate-promise-for-the-treatment-of-dry-eye-disease-and-other-ocular-inflammatory-disorders
#14
Suzanne Hagan, Matthew C T Fyfe, Boatemaa Ofori-Frimpong, Katherine Oliver, Martyn R Foster, Sameer Sirohi, Yemisi Solanke, Michael Doughty, Adele Rowley, Mike Taylor, Steve Webber, Claire A Walshe
Purpose: The purpose of this study is to determine the potential of narrow spectrum kinase inhibitors (NSKIs) to treat inflammatory eye disorders. Methods: Human conjunctival epithelial (HCE) cells were retrieved from subjects via impression cytology. Real-time quantitative PCR (qPCR) was performed on HCE cells to determine gene expression of NSKI kinase targets and proinflammatory cytokines in dry eye disease (DED) patients versus healthy controls. qPCR also assessed p38α expression in hyperosmolar-treated Chang conjunctival epithelial cells...
March 1, 2018: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29623489/bi1-is-associated-with-microvascular-protection-in-cardiac-ischemia-reperfusion-injury-via-repressing-syk-nox2-drp1-mitochondrial-fission-pathways
#15
Hao Zhou, Chen Shi, Shunying Hu, Hong Zhu, Jun Ren, Yundai Chen
BACKGROUND: Mitochondrial fission has been identified as the pathogenesis underlying the development of cardiac microvascular ischemia reperfusion (IR) injury, although the regulatory signaling upstream from fission is far from clear. Bax inhibitor is a novel anti-apoptotic factor, and, however, its role of cardiac microvascular IR injury and mitochondrial homeostasis remains unclear. METHODS: The cardiac microvascular IR injury was performed in WT mice and BI1 transgenic (BITG ) mice...
April 6, 2018: Angiogenesis
https://www.readbyqxmd.com/read/29611449/splenic-tyrosine-kinase-syk-inhibitors-and-their-possible-use-in-acute-myeloid-leukemia
#16
Sushma Bartaula-Brevik, Marte Karen Lindstad Brattås, Tor Henrik Anderson Tvedt, Håkon Reikvam, Øystein Bruserud
Splenic tyrosine kinase (SYK) is a non-receptor tyrosine kinase. It is important for downstream signaling from several cell surface receptors, including Fc receptors, complement receptors and integrins. SYK can have either oncogenic or tumor suppressor activity in human malignancies. Recent studies suggest that SYK inhibition may have an antileukemic effect in human acute myeloid leukemia (AML). Areas covered: Relevant publications were identified through literature searches in the PubMed database. We searched for (i) original articles describing the results from clinical studies of SYK inhibition; (ii) published articles describing the importance of SYK in human malignancies, especially AML...
April 4, 2018: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29578342/isolation-characterization-and-structure-activity-relationship-analysis-of-abietane-diterpenoids-from-callicarpa-bodinieri-as-spleen-tyrosine-kinase-inhibitors
#17
Jun-Bo Gao, Shuang-Jing Yang, Zi-Ru Yan, Xing-Jie Zhang, De-Bing Pu, Li-Xia Wang, Xiao-Li Li, Rui-Han Zhang, Wei-Lie Xiao
Species belonging to the genus Callicarpa are used traditionally in Chinese medicine for the treatment of inflammation, rheumatism, and pain. Investigation of the leaves and twigs of Callicarpa bodinieri resulted in the isolation of nine new abietane diterpenoids, bodinieric acids A-I (1-9), along with six known compounds (10-15). The structures of 1-9 were elucidated on the basis of the interpretation of their HRESIMS and NMR data and by ECD calculations. To explore the potential therapeutic target of this plant for immune-mediated disease, the inhibitory activities of the isolates obtained were determined against 13 kinase enzymes...
March 26, 2018: Journal of Natural Products
https://www.readbyqxmd.com/read/29545260/involvement-of-b-cells-immunoglobulins-and-syk-in-the-pathogenesis-of-abdominal-aortic-aneurysm
#18
Aya Furusho, Hiroki Aoki, Satoko Ohno-Urabe, Michihide Nishihara, Saki Hirakata, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Tsutomu Imaizumi, Shinichi Hiromatsu, Hidetoshi Akashi, Hiroyuki Tanaka, Yoshihiro Fukumoto
BACKGROUND: Abdominal aortic aneurysm (AAA) is a potentially life-threatening disease that is common in older individuals. Currently, therapeutic options are limited to surgical interventions. Although it has long been known that AAA tissue is enriched in B cells and immunoglobulins, their involvement in AAA pathogenesis remains controversial. METHODS AND RESULTS: We investigated the role of B cells and immunoglobulins in a murine model of AAA, induced with a periaortic application of CaCl2 , and in human AAA...
March 15, 2018: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29540860/dectin-1-stimulates-il-33-expression-in-dendritic-cells-via-upregulation-of-irf4
#19
Dongjiao Wang, Sujun Gao, Jintong Chen, Yinghua Zhao, Yuxue Jiang, Xiao Chu, Xiaohua Wang, Ning Liu, Tianxue Qin, Qing Yi, Ying Yue, Siqing Wang
Interleukin-33 (IL-33) is a potent contributor to antiviral immune responses and antitumor immunity. We recently discovered that IL-33 is overexpressed in dectin-1-activated dendritic cells (DCs). However, mechanisms of dectin-1-induced IL-33 expression in DCs remain elusive. Curdlan, an agonist of dectin-1, was used to mature DCs in this study. We found that dectin-1-induced IL-33 expression in DCs relies on Syk and Raf-1 pathways. By using nuclear factor (NF)-κB inhibitors, we also found that dectin-1-induced IL-33 expression relies on NF-κB signaling...
March 14, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29491142/aspartyl-proteases-in-candida-glabrata-are-required-for-suppression-of-the-host-innate-immune-response
#20
Mubashshir Rasheed, Anamika Battu, Rupinder Kaur
A family of 11 cell surface-associated aspartyl proteases (CgYps1-11), also referred as yapsins, is a key virulence factor in the pathogenic yeast Candida glabrata However, the mechanism by which CgYapsins modulate immune response and facilitate survival in the mammalian host remains to be identified. Here, using RNA-Seq analysis, we report that genes involved in cell wall metabolism are differentially regulated in the Cgyps1-11 Δ mutant. Consistently, the mutant contained lower β-glucan and mannan levels and exhibited increased chitin content in the cell wall...
April 27, 2018: Journal of Biological Chemistry
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