Syk pathway cancer

Spleen tyrosine kinase (Syk) is a key signal transduction mediator of the B cell receptor (BCR) signaling pathway. Abnormal BCR signaling plays a key role in initiation and development of B-cell-derived hematological malignancies, therefore, Syk represents a potential target for inhibiting the BCR signaling resulting in a therapeutic effect in these cancers. Herein, we describe a novel series of SYK inhibitors with 4-(3'-pyrazolyl)-2-amino-pyrimidine scaffold. Extensive study of structure-activity relationships led to the identification of 1 (NMS-0963), a highly potent Syk inhibitor (IC50  = 3 nM) endowed with high selectivity within a panel of tested kinases and high antiproliferative activity in SYK-dependent BaF3-TEL/SYK cells and in other BCR-dependent hematological tumor cell lines...

BACKGROUND: Podoplanin (PDPN) expressed on tumour cells interacts with platelet C-type lectin-like receptor 2 (CLEC-2). This study aimed to investigate the role of the PDPN-platelet CLEC-2 interaction in melanoma pulmonary metastasis. METHODS: Murine melanoma B16-F0 cells, which have two populations that express podoplanin, were sorted by FACS with anti-podoplanin staining to obtain purified PDPN + and PDPN- B16-F0 cells. C57BL/6J mice transplanted with CLEC-2-deficient bone marrow cells were used for in vivo experiments...

Nonspecific structural chromosomal aberrations (CAs) are found in around 1% of circulating lymphocytes from healthy individuals but the frequency may be higher after exposure to carcinogenic chemicals or radiation. CAs have been used in the monitoring of persons exposed to genotoxic agents and radiation. Previous studies on occupationally exposed individuals have shown associations between the frequency of CAs in peripheral blood lymphocytes and subsequent cancer risk. The cause for CA formation are believed to be unrepaired or insufficiently repaired DNA double-strand breaks or other DNA damage, and additionally telomere shortening...

Bruton's tyrosine kinase (BTK) is a non-RTK cytoplasmic kinase predominantly expressed by hemopoietic lineages, particularly B-cells. A new oxindole-based focused library was designed to identify potent compounds targeting the BTK protein as anticancer agents. This study used rational approaches like structure-based pharmacophore modeling, docking, and ADME properties to select compounds. Molecular dynamics simulations carried out at 20 ns supported the stability of compound 9g within the binding pocket. All the compounds were synthesized and subjected to biological screening on two BTK-expressing cancer cell lines, RAMOS and K562; six non-BTK cancer cell lines, A549, HCT116 (parental and p53-/- ), U2OS, JURKAT, and CCRF-CEM; and two non-malignant fibroblast lines, BJ and MRC-5...

BACKGROUND: Glioblastomas (GBMs) are central nervous system tumors that resist standard of care interventions and even immune checkpoint blockade. Myeloid cells in the tumor microenvironment can contribute to GBM progression; therefore, emerging immunotherapeutic approaches include reprogramming these cells to achieve desirable anti-tumor activity. Triggering receptor expressed on myeloid cells 2 (TREM2) is a myeloid signaling regulator that has been implicated in a variety of cancers and neurological diseases with contrasting functions, but its role in GBM immunopathology and progression is still under investigation...

OBJECTIVE: To investigate the effect of ARL67156, a small-molecule inhibitor of CD39, on cytotoxicity of natural killer (NK) cells against gastric cancer cells. METHODS: Human peripheral blood-derived primary NK cells isolated and purified using a magnetic bead antibody method were treated with 100 μmol/L ARL67156 for 24 h, and the signaling pathway of NK cell activation was detected by Western blotting. The level of interferon-γ (IFN-γ) in the supernatant of NK cells co-cultured with gastric cancer cells was detected using ELISA, and NK cell CD107a degranulation was measured with flow cytometry...

With the development of immunotherapy, the process of tumor treatment is also moving forward. Polysaccharides are biological response modifiers widely found in plants, animals, fungi, and algae and are mainly composed of monosaccharides covalently linked by glycosidic bonds. For a long time, polysaccharides have been widely used clinically to enhance the body's immunity. However, their mechanisms of action in tumor immunotherapy have not been thoroughly explored. Dendritic cells (DCs) are a heterogeneous population of antigen presenting cells (APCs) that play a crucial role in the regulation and maintenance of the immune response...

Solanum xanthocarpum (SX) has been used to treat a variety of diseases, including skin disorders like psoriasis (PSO). SX possesses many pharmacological activities of anti-inflammatory, anti-cancer, immunosuppressive, and healing qualities. However, the multi-target mechanism of SX on PSO still needs clarity. Materials and methods: The Indian Medicinal Plants, Phytochemicals and Therapeutics (IMPPAT) database and the Swiss Target Prediction online tool were used to find the active phytochemical components and their associated target proteins...

Papillary thyroid cancer (PTC) is a prevalent malignancy worldwide. Spleen tyrosine kinase (SYK) is a crucial enzyme that participates in various biological processes, including cancer progression. This study aims to uncover the biological function of SYK in PTC. SYK expression patterns in PTC were evaluated using quantitative real time polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), and western blot. Cell function assays were performed to assess the effects of SYK on PTC. Bioinformatics analysis was conducted to identify intriguing microRNA (miRNA) and circular RNA (circRNA)...

TAK1 is a key modulator of both NF-κB signaling and RIPK1. In TNF signaling pathway, activation of TAK1 directly mediates the phosphorylation of IKK complex and RIPK1. In a search for small molecule activators of RIPK1-mediated necroptosis, we found R406/R788, two small molecule analogs that could promote sustained activation of TAK1. Treatment with R406 sensitized cells to TNF-mediated necroptosis and RIPK1-dependent apoptosis by promoting sustained RIPK1 activation. Using click chemistry and multiple biochemical binding assays, we showed that treatment with R406 promotes the activation of TAK1 by directly binding to TAK1, independent of its original target Syk kinase...

Inflammation is a protective mechanism against harmful stimuli. There are two types of inflammation, acute and chronic, and severe diseases such as cardiovascular disease and cancer can be caused by chronic inflammation. Therefore, this research was conducted to discover new anti-inflammatory drugs. Meriania hexamera Sprague is a common herb in the Amazon region in South America. It is used as a traditional medical herb by natives, but no studies to date have investigated its anti-inflammatory activity. Using lipopolysaccharide (LPS), pam3CSK4 (Pam3), and poly(I:C), we studied the M...

BACKGROUND: The high prevalence of chronic inflammatory diseases or autoimmune reactions is a major source of concern and affects the quality of life of patients. Chronic inflammatory or autoimmune diseases are associated with many diseases in humans, including asthma, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and cancer. Splenic tyrosine kinase (SYK) is a non-receptor tyrosine kinase that plays an important role in immune receptor signalling in immune and inflammatory responses...

Spleen tyrosine kinase (Syk) is an important oncogene and signal transduction mediator that is mainly expressed in hematopoietic cells. Syk plays a key role in the B cell receptor (BCR) signaling pathway. Abnormal activation of Syk is closely related to the occurrence and development of hematological malignancies. Therefore, Syk is a potential target for the treatment of various hematologic cancers. Starting from compound 6(Syk, IC50  = 15.8 μM), we performed fragment-based rational drug design for structural optimization based on the specific solvent-accessible region, hydrophobic region, and ribose region of Syk...

Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase known to regulate immune cell function, cell adhesion, and vascular development. Here, we report that Syk can be expressed in high grade serous ovarian cancer and triple negative breast cancers and promotes DNA double strand break resection, homologous recombination (HR) and therapeutic resistance...

The Raptor signaling pathway is a critical point of intervention in the invasion and progression of cancer. The non-receptor tyrosine kinase Src-mediated phosphorylation of OTUB1-Y26 plays a critical role in Raptor stabilization, whereas cathepsin K inhibitor (odanacatib; ODN) and knockdown (siRNA) induce Raptor destabilization. However, the mechanisms involved in cathepsin K inhibition-induced OTUB1-Y26 phosphorylation in Raptor stabilization have not been yet elucidated. This study showed that cathepsin K inhibition activates SHP2, a tyrosine phosphatase, that dephosphorylates OTUB1 and destabilizes Raptor, whereas SHP2 deletion and pharmacological inhibition increase OTUB1-Y26 phosphorylation and Raptor expression...

BACKGROUND: Immune checkpoint inhibition (ICI) has improved clinical outcomes for metastatic melanoma patients; however, 65-80% of patients treated with ICI experience immune-related adverse events (irAEs). Given the plausible link of irAEs with underlying host immunity, we explored whether germline genetic variants controlling the expression of 42 immunomodulatory genes were associated with the risk of irAEs in melanoma patients treated with the single-agent anti-CTLA-4 antibody ipilimumab (IPI)...

Proline residues highly impact protein stability when present either in the first or second N-terminal position. While the human genome encodes for more than 500 proteases, only few proteases are capable of hydrolyzing a proline-containing peptide bond. The two intra-cellular amino-dipeptidyl peptidases DPP8 and DPP9 are exceptional as they possess the rare ability to cleave post-proline. By removing N-terminal Xaa-Pro dipeptides, DPP8 and DPP9 expose a neo N-terminus of their substates, which can consequently alter inter- or intra-molecular interactions of the modified protein...

Glioblastoma (GBM) is an aggressive brain cancer with a median survival time of 14.6 months after diagnosis. GBM cells have altered metabolism and exhibit the Warburg effect, preferentially producing lactate under aerobic conditions. After standard-of-care treatment for GBM, there is an almost 100% recurrence rate. Hypoxia-adapted, treatment-resistant GBM stem-like cells are thought to drive this high recurrence rate. We used human T98G GBM cells as a model to identify differential gene expression induced by hypoxia and to search for potential therapeutic targets of hypoxia adapted GBM cells...

Lenvatinib is a multitarget tyrosine kinase inhibitor (TKI) approved for the treatment of several types of cancers, including metastatic differentiated thyroid cancer (DTC). The intended targets include VEGFR 1-3, FGFR 1-4, PDGFRα, RET, and KIT signaling pathways, but drug resistance inevitably develops and a complete cure is very rare. Recent data has revealed that most of the TKIs have additional 'off-target' immunological effects, which might contribute to a protective antitumor immune response; however, human cellular data are lacking regarding Lenvatinib-mediated immunomodulation in DTC...

Allergy is a chronic inflammatory disease, and its incidence has increased worldwide in recent years. Thalidomide, which was initially used as an anti-emetic drug but was withdrawn due to its teratogenic effects, is now used to treat blood cancers. Although the anti-inflammatory and immunomodulatory properties of thalidomide have been reported, little is known about its influence on the mast cell-mediated allergic reaction. In the present study, we aimed to evaluate the anti-allergic activity of thalidomide and the underlying mechanism using mouse bone marrow-derived mast cells (BMMCs) and passive cutaneous anaphylaxis (PCA) mouse models...