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Syk inhibitor

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https://www.readbyqxmd.com/read/28405610/btk-specific-inhibition-blocks-pathogenic-plasma-cell-signatures-and-myeloid-cell-associated-damage-in-ifn%C3%AE-driven-lupus-nephritis
#1
Arna Katewa, Yugang Wang, Jason A Hackney, Tao Huang, Eric Suto, Nandhini Ramamoorthi, Cary D Austin, Meire Bremer, Jacob Zhi Chen, James J Crawford, Kevin S Currie, Peter Blomgren, Jason DeVoss, Julie A DiPaolo, Jonathan Hau, Adam Johnson, Justin Lesch, Laura E DeForge, Zhonghua Lin, Marya Liimatta, Joseph W Lubach, Sami McVay, Zora Modrusan, Allen Nguyen, Chungkee Poon, Jianyong Wang, Lichuan Liu, Wyne P Lee, Harvey Wong, Wendy B Young, Michael J Townsend, Karin Reif
Systemic lupus erythematosus (SLE) is often associated with exaggerated B cell activation promoting plasma cell generation, immune-complex deposition in the kidney, renal infiltration of myeloid cells, and glomerular nephritis. Type-I IFNs amplify these autoimmune processes and promote severe disease. Bruton's tyrosine kinase (Btk) inhibitors are considered novel therapies for SLE. We describe the characterization of a highly selective reversible Btk inhibitor, G-744. G-744 is efficacious, and superior to blocking BAFF and Syk, in ameliorating severe lupus nephritis in both spontaneous and IFNα-accelerated lupus in NZB/W_F1 mice in therapeutic regimens...
April 6, 2017: JCI Insight
https://www.readbyqxmd.com/read/28391340/targeting-the-tyrosine-kinase-signalling-pathways-for-treatment-of-immune-mediated-glomerulonephritis-from-bench-to-bedside-and-beyond
#2
Terry King-Wing Ma, Stephen P McAdoo, Frederick Wai Keung Tam
Glomerulonephritis (GN) affects patients of all ages and is an important cause of morbidity and mortality. Non-selective immunosuppressive drugs have been used in immune-mediated GN but often result in systemic side effects and occasionally fatal infective complications. There is increasing evidence from both preclinical and clinical studies that abnormal activation of receptor and non-receptor tyrosine kinase signalling pathways are implicated in the pathogenesis of immune-mediated GN. Activation of spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR) and discoidin domain receptor 1 (DDR1) have been demonstrated in anti-GBM disease...
January 1, 2017: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/28385506/divergent-synthesis-of-kinase-inhibitor-derivatives-leading-to-discovery-of-selective-gck-inhibitors
#3
Takanori Matsumaru, Makoto Inai, Kana Ishigami, Toshiki Iwamatsu, Hiroshi Maita, Satoko Otsuguro, Takao Nomura, Akira Matsuda, Satoshi Ichikawa, Masahiro Sakaitani, Satoshi Shuto, Katsumi Maenaka, Toshiyuki Kan
We accomplished divergent synthesis of potent kinase inhibitor BAY 61-3606 (1) and 27 derivatives via conjugation of imidazo[1,2-c]pyrimidine and indole ring compounds with aromatic (including pyridine) derivatives by means of palladium-catalyzed cross-coupling reaction. Spleen tyrosine kinase (Syk) and germinal center kinase (Gck, MAP4K2) inhibition assays showed that some of the synthesized compounds were selective Gck inhibitors.
March 23, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28359287/activity-of-the-novel-bcr-kinase-inhibitor-iqs019-in-preclinical-models-of-b-cell-non-hodgkin-lymphoma
#4
P Balsas, A Esteve-Arenys, J Roldán, L Jiménez, V Rodríguez, J G Valero, A Chamorro-Jorganes, R Puig de la Bellacasa, J Teixidó, A Matas-Céspedes, A Moros, A Martínez, E Campo, A Sáez-Borderías, J I Borrell, P Pérez-Galán, D Colomer, G Roué
BACKGROUND: Pharmacological inhibition of B cell receptor (BCR) signaling has recently emerged as an effective approach in a wide range of B lymphoid neoplasms. However, despite promising clinical activity of the first Bruton's kinase (Btk) and spleen tyrosine kinase (Syk) inhibitors, a small fraction of patients tend to develop progressive disease after initial response to these agents. METHODS: We evaluated the antitumor activity of IQS019, a new BCR kinase inhibitor with increased affinity for Btk, Syk, and Lck/Yes novel tyrosine kinase (Lyn), in a set of 34 B lymphoid cell lines and primary cultures, including samples with acquired resistance to the first-in-class Btk inhibitor ibrutinib...
March 31, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28350104/induction-of-galectin-1-by-tlr-dependent-pi3k-activation-enhances-epithelial-mesenchymal-transition-of-metastatic-ovarian-cancer-cells
#5
Ga Bin Park, Yoon Hee Chung, Daejin Kim
The expression of different toll-like receptors (TLRs) on tumor cells has been associated with disease aggressiveness, treatment resistance, and poor prognosis. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is considered critical for cancer cell survival and proliferation. Thus, we investigated the effect of TLR-stimulated PI3K activation on the epithelial-to-mesenchymal transition (EMT) of primary (Caov-3) and metastatic (SK‑OV‑3) epithelial ovarian cancer cell lines in this study. TLR engagement with various ligands promoted the expression of class IA PI3K (p110α, p110β, and p110δ) and increased the expression of mesenchymal markers (N-cadherin, Slug, Vimentin, Snail, α-SMA, and TCF) in SK‑OV‑3 cells...
March 27, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28336564/identification-of-a-novel-syk-c-myc-malat1-signaling-pathway-and-its-potential-therapeutic-value-in-ewing-sarcoma
#6
Haibo Sun, De-Chen Lin, Qi Cao, Brendan Pang, David D Gae, Victor Km Lee, Huey Jin Lim, Ngan Doan, Jonathan W Said, Sigal Gery, Marilynn Chow, Anand Mayakonda, Charles Forscher, Jeffrey W Tyner, H Phillip Koeffler
PURPOSE: Ewing Sarcoma (EWS) is a devastating soft tissue sarcoma affecting predominantly young individuals. Tyrosine kinases (TKs) and associated pathways are continuously activated in many malignancies including EWS; these enzymes provide candidate therapeutic targets. EXPERIMENTAL DESIGN: Two high-throughput screens (a siRNA library and a small-molecule inhibitor library) were performed in EWS cells to establish candidate targets. Spleen tyrosine kinase (SYK) phosphorylation was assessed in EWS patients and cell lines...
March 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28336561/mice-lacking-the-inhibitory-collagen-receptor-lair-1-exhibit-a-mild-thrombocytosis-and-hyperactive-platelets
#7
Christopher W Smith, Steven G Thomas, Zaher Raslan, Pushpa Patel, Maxwell Byrne, Marie Lordkipanidzé, Danai Bem, Linde Meyaard, Yotis A Senis, Steve P Watson, Alexandra Mazharian
OBJECTIVE: Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a collagen receptor that belongs to the inhibitory immunoreceptor tyrosine-based inhibition motif-containing receptor family. It is an inhibitor of signaling via the immunoreceptor tyrosine-based activation motif-containing collagen receptor complex, glycoprotein VI-FcRγ-chain. It is expressed on hematopoietic cells, including immature megakaryocytes, but is not detectable on platelets. Although the inhibitory function of LAIR-1 has been described in leukocytes, its physiological role in megakaryocytes and in particular in platelet formation has not been explored...
March 23, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28335387/dectin-1-mediated-pathway-contributes-to-fusarium-proliferatum-induced-cxcl-8-release-from-human-respiratory-epithelial-cells
#8
Chang-Ching Yeh, Huann-Cheng Horng, Hong Chou, Hsiao-Yun Tai, Horng-Der Shen, Shie-Liang Hsieh, Peng-Hui Wang
Fusarium species are causative agents of human respiratory disorders and are distributed widely in our environment. Little is known of their interaction with human respiratory epithelial cells, which may contribute to allergic airway responses. In this study, we report on the release of C-X-C motif chemokine ligand 8 (CXCL-8) from human bronchial epithelial BEAS-2B cells upon stimulation with Fusarium proliferatum extracts. F. proliferatum-induced cytokine release from BEAS-2B cells was determined by cytokine array and CXCL-8 enzyme-linked immunosorbent assay (ELISA) kits...
March 13, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28326700/-in-vitro-investigation-on-the-mechanism-of-cyclooxygenase-2-upregulation-induced-by-spleen-tyrosine-kinase-nuclear-factor-%C3%AE%C2%BAb-signaling-in-cancer-pain-caused-by-oral-cancer-associated-macrophage
#9
Lin Jie, Wang Miao, Ji Yang, Liu Le, Gao Pan, Li Chunjie
OBJECTIVE: This study explores the mechanism of cyclooxygenase-2 (COX-2) upregulation in oral cancers associated with macrophage by using molecular biology techniques and primary culture of murine macrophage. METHODS: Murine macrophage was induced by macrophage colony-stimulating factor (M-CSF) and Cal27 conditional medium (CM). Purity of the macrophage was detected through CD68 immunofluorescence staining. Inhibitors of spleen tyrosine kinase (Syk) and nuclear factor κB (NFκB) were used to inhibit these pathways...
October 1, 2016: Hua Xi Kou Qiang Yi Xue za Zhi, Huaxi Kouqiang Yixue Zazhi, West China Journal of Stomatology
https://www.readbyqxmd.com/read/28293439/proteomic-analysis-of-hdac3-selective-inhibitor-in-the-regulation-of-inflammatory-response-of-primary-microglia
#10
Mingxu Xia, Qiuchen Zhao, He Zhang, Yanting Chen, Zengqiang Yuan, Yun Xu, Meijuan Zhang
HDAC3 has been shown to regulate inflammation. However, the role of HDAC3 in primary microglia is largely unknown. RGFP966 is a newly discovered selective HDAC3 inhibitor. In this study, we used protein mass spectrometry to analyze protein alterations in LPS-treated primary microglia with the application of RGFP966. Generally, about 2000 proteins were studied. 168 of 444 (37.8%) LPS-induced proteins were significantly reduced with the treatment of RGFP966, which mainly concentrated on Toll-like receptor signaling pathway...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/28291124/myc-protein-positive-diffuse-large-b-cell-lymphoma-features-an-activated-b-cell-receptor-signal-pathway
#11
Wei-Ge Wang, Xiang-Nan Jiang, Ze-Bing Liu, Xiao-Yan Zhou, Xiao-Qiu Li
Components of the B-cell receptor (BCR) signaling pathway represent promising therapeutic targets in diffuse large B-cell lymphoma (DLBCL) and other B-cell malignancies. MYC, a transcriptional factor and oncoprotein, is overexpressed in a fraction of DLBCL and indicates poor prognosis and aggressive clinical course when treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, BCR signaling status in MYC-positive DLBCL cases and the potential efficacy of BCR signal inhibitors in treating this aggressive disease are unknown...
April 2017: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/28268139/discovery-of-new-syk-inhibitors-through-structure-based-virtual-screening
#12
Yahui Huang, Youjun Zhang, Kexin Fan, Guoqiang Dong, Bohua Li, Wannian Zhang, Jian Li, Chunquan Sheng
Spleen tyrosine kinase (Syk) is an attractive target for the discovery of new treatments for inflammatory and autoimmune disorders. Structure-based virtual screening was performed for identifying novel scaffolds of Syk inhibitors. A total of 16 hits were discovered in the enzyme assay and 8 compounds had an IC50 value lower than 10μM. In particular, compound 11 (IC50=3.2μM) was active in the cellular Syk assay and could inhibit lymphocytes proliferation in a dose-dependent manner, which could be used as a good starting point for the discovery of new class of Syk inhibitors...
February 24, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28259713/jte-852-a-novel-spleen-tyrosine-kinase-inhibitor-blocks-mediator-secretion-from-mast-cells-with-immunoglobulin-e-crosslinking
#13
Toshinobu Kato, Hidenori Iwasaki, Hatsue Kobayashi, Naoki Miyagawa, Akira Matsuo, Takahiro Hata, Mutsuyoshi Matsushita
Mast cells stimulated by immunoglobulin E (IgE)-crosslinking secrete mediators, which are mainly categorized into three groups: granule contents, arachidonate metabolites, and cytokines. These mediators play important roles in pathogenesis of allergic diseases; indeed, some conventional drugs which target the mediators are used in clinical practices. However, these drugs are not yet sufficient enough in their efficacy. That is because most of them are blockers of single mediators and are unable to prevent simultaneously various reactions caused by the three group mediators...
April 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28245410/-research-progress-of-novel-small-molecule-drugs-in-the-treatment-of-chronic-lymphocytic-leukemia-review
#14
Jing-Qiao Qiao, Miao He, Shu-Ting Zhang, Hai Bai
Chronic lymphocytic leukemia (CLL), the most frequent adult leukemia in Western population, is characterized by accumulation of mature-looking CD5(+)/19(+)/23(+) B cells in peripheral blood, bone marrow, and lymphatic organs. Over the last 20 years, there has been a dramatic change in therapy for CLL, the complete response rate increased from the initial <5% to the current 40%-50%, this remarkable improvement has been attributable to combination of chemoimmunotherapy agents that have contributed to the backbone of therapy for patients with CLL...
February 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28217127/cell-intrinsic-galectin-3-attenuates-neutrophil-ros-dependent-killing-of-candida-by-modulating-cr3-downstream-syk-activation
#15
Sheng-Yang Wu, Juin-Hua Huang, Wen-Yu Chen, Yi-Chen Chan, Chun-Hung Lin, Yee-Chun Chen, Fu-Tong Liu, Betty A Wu-Hsieh
Invasive candidiasis is a leading cause of nosocomial bloodstream infection. Neutrophils are the important effector cells in host resistance to candidiasis. To investigate the modulation of neutrophil fungicidal function will advance our knowledge on the control of candidiasis. While recombinant galectin-3 enhances neutrophil phagocytosis of Candida, we found that intracellular galectin-3 downregulates neutrophil fungicidal functions. Co-immunoprecipitation and immunofluorescence staining reveal that cytosolic gal3 physically interacts with Syk in neutrophils after Candida stimulation...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28202529/aberrant-syk-kinase-signaling-is-essential-for-tumorigenesis-induced-by-tsc2-inactivation
#16
Ye Cui, Wendy K Steagall, Anthony M Lamattina, Gustavo Pacheco-Rodriguez, Mario Stylianou, Pranav Kidambi, Benjamin Stump, Fernanda Golzarri, Ivan O Rosas, Carmen Priolo, Elizabeth P Henske, Joel Moss, Souheil El-Chemaly
Somatic or germline mutations in the tuberous sclerosis complex (TSC) tumor suppressor genes are associated closely with the pathogenesis of lymphangioleiomyomatosis, a rare and progressive neoplastic disease that predominantly affects women in their childbearing years. Serum levels of the lymphangiogenic growth factor VEGF-D are elevated significantly in lymphangioleiomyomatosis. However, there are gaps in knowledge regarding VEGF-D dysregulation and its cellular origin in lymphangioleiomyomatosis. Here, we show that increased expression and activation of the tyrosine kinase Syk in TSC2-deficient cells and pulmonary nodules from lymphangioleiomyomatosis patients contributes to tumor growth...
March 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28179537/early-tyrosine-phosphorylation-events-following-adenosine-a2a-receptor-in-human-neutrophils-identification-of-regulated-pathways
#17
Miriam S Giambelluca, Marc Pouliot
Activation of the adenosine 2A receptor (A2AR) elevates intracellular levels of cAMP and acts as a physiologic inhibitor of inflammatory neutrophil functions. In this study, we looked into the impact of A2AR engagement on early phosphorylation events. Neutrophils were stimulated with well-characterized proinflammatory agonists in the absence or presence of an A2AR agonist {3-[4-[2-[ [6-amino-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]purin-2-yl]amino] ethyl] phenyl] propanoic acid (CGS 21680)}, PGE2, or a mixture of the compounds RO 20-1724 and forskolin...
February 8, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28178976/advanced-glycation-end-products-induce-brain-derived-neurotrophic-factor-release-from-human-platelets-through-the-src-family-kinase-activation
#18
Kazuo Furukawa, Ichiro Fuse, Yuriko Iwakura, Hidekazu Sotoyama, Osamu Hanyu, Hiroyuki Nawa, Hirohito Sone, Nobuyuki Takei
BACKGROUND: Brain-derived neurotrophic factor (BDNF) exerts beneficial effects not only on diabetic neuropathies but also on cardiovascular injury. There is argument regarding the levels of serum BDNF in patients with diabetes mellitus (DM). Because BDNF in peripheral blood is rich in platelets, this may represent dysregulation of BDNF release from platelets. Here we focused on advanced glycation end products (AGEs), which are elevated in patients with DM and have adverse effects on cardiovascular functions...
February 8, 2017: Cardiovascular Diabetology
https://www.readbyqxmd.com/read/28173838/osteoarthritis-associated-basic-calcium-phosphate-crystals-activate-membrane-proximal-kinases-in-human-innate-immune-cells
#19
Emma M Corr, Clare C Cunningham, Laura Helbert, Geraldine M McCarthy, Aisling Dunne
BACKGROUND: Osteoarthritis (OA) is a chronic debilitating joint disorder of particularly high prevalence in the elderly population. Intra-articular basic calcium phosphate (BCP) crystals are present in the majority of OA joints and are associated with severe degeneration. They are known to activate macrophages, synovial fibroblasts, and articular chondrocytes, resulting in increased cell proliferation and the production of pro-inflammatory cytokines and matrix metalloproteases (MMPs)...
February 7, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28147336/dual-inhibition-of-histone-deacetylases-and-phosphoinositide-3-kinase-enhances-therapeutic-activity-against-b-cell-lymphoma
#20
Patrizia Mondello, Enrico Derenzini, Zahra Asgari, John Philip, Elliott J Brea, Venkatraman Seshan, Ronald C Hendrickson, Elisa de Stanchina, David A Scheinberg, Anas Younes
Phosphoinositide 3-kinase (PI3K) and Myc are known to cooperate in promoting the survival and growth of a variety of B-cell lymphomas. While currently there are no small molecule inhibitors of Myc protein, histone deacetylase (HDAC) inhibitors have been shown to reduce levels of Myc protein by suppressing its transcription. We assessed the efficacy of CUDC-907, a new rationally designed dual inhibitor of PI3K and HDACs, in a panel of lymphoma cell lines. CUDC-907 treatment resulted in a dose- and time-dependent growth inhibition and cell death of DLBCL cell lines, irrespective of the cell of origin...
February 21, 2017: Oncotarget
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