scholarly journals Docking studies to explore novel lead molecules for human Spleen tyrosine kinase involved in chronic lymphocytic leukemia

2010 ◽  
Author(s):  
Naveen Kadaari ◽  
Dibyabhaba Pradhan ◽  
Manne Munikumar ◽  
Amineni Umamaheswari
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
Docking Studies ◽  
Lymphocytic Leukemia ◽  
Spleen Tyrosine Kinase ◽  
Human Spleen

scholarly journals B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406

Blood ◽  
2009 ◽  
Vol 114 (5) ◽  
pp. 1029-1037 ◽  
Author(s):  
Maite P. Quiroga ◽  
Kumudha Balakrishnan ◽  
Antonina V. Kurtova ◽  
Mariela Sivina ◽  
Michael J. Keating ◽  
...  
Keyword(s):  
Cell Migration ◽  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Antigen Receptor ◽  
Lymphocytic Leukemia ◽  
B Cell Antigen Receptor ◽  
Spleen Tyrosine Kinase ◽  
Cell Antigen Receptor ◽  
Cell Antigen

Antigenic stimulation through the B-cell antigen receptor (BCR) is considered to promote the expansion of chronic lymphocytic leukemia (CLL) B cells. The spleen tyrosine kinase (Syk), a key component of BCR signaling, can be blocked by R406, a small-molecule Syk inhibitor, that displayed activity in CLL patients in a first clinical trial. In this study, we investigated the effects of BCR stimulation and R406 on CLL cell survival and migration. The prosurvival effects promoted by anti-IgM stimulation and nurselike cells were abrogated by R406. BCR triggering up-regulated adhesion molecules, and increased CLL cell migration toward the chemokines CXCL12 and CXCL13. BCR activation also enhanced CLL cell migration beneath marrow stromal cells. These responses were blocked by R406, which furthermore abrogated BCR-dependent secretion of T-cell chemokines (CCL3 and CCL4) by CLL cells. Finally, R406 inhibited constitutive and BCR-induced activation of Syk, extracellular signal-regulated kinases, and AKT, and blocked BCR-induced calcium mobilization. These findings suggest that BCR activation favors CLL cell homing, retention, and survival in tissue microenvironments. R406 effectively blocks these BCR-dependent responses in CLL cells, providing an explanation for the activity of R406 in patients with CLL.

Spleen tyrosine kinase inhibition prevents chemokine- and integrin-mediated stromal protective effects in chronic lymphocytic leukemia

Blood ◽  
2010 ◽  
Vol 115 (22) ◽  
pp. 4497-4506 ◽  
Author(s):  
Maike Buchner ◽  
Constance Baer ◽  
Gabriele Prinz ◽  
Christine Dierks ◽  
Meike Burger ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Cytotoxic Agents ◽  
Protective Effects ◽  
Spleen Tyrosine Kinase ◽  
Growth And Survival ◽  
Akt Phosphorylation ◽  
Bcr Signaling

Abstract The microenvironment provides essential growth and survival signals to chronic lymphocytic leukemia (CLL) cells and contributes to their resistance to cytotoxic agents. Pharmacologic inhibition of spleen tyrosine kinase (SYK), a key mediator of B-cell receptor (BCR) signaling, induces apoptosis in primary CLL cells and prevents stroma contact-mediated cell survival. This report demonstrates a role of SYK in molecularly defined pathways that mediate the CLL-microenvironmental crosstalk independent from the BCR. Chemokine and integrin stimulation induced SYK phosphorylation, SYK-dependent Akt phosphorylation, and F-actin formation in primary CLL cells. Inhibition of SYK by 2 pharmacologic inhibitors and siRNA-knockdown abrogated downstream SYK signaling and morphologic changes induced by these stimuli. CLL cell migration toward CXCL12, the major homing attractor, and CLL cell adhesion to VCAM-1, a major integrin ligand expressed on stromal cells, were markedly reduced by SYK inhibition. In combination with fludarabine, the SYK inhibitor R406 abrogated stroma-mediated drug resistance by preventing up-regulation of the antiapoptotic factor Mcl-1 in CLL cells. SYK blockade in CLL is a promising therapeutic principle not only for its inhibition of the BCR signaling pathway, but also by inhibiting protective stroma signals in a manner entirely independent of BCR signaling.

scholarly journals Spleen Tyrosine Kinase Is Overexpressed and Represents a Potential Therapeutic Target in Chronic Lymphocytic Leukemia

2009 ◽  
Vol 69 (13) ◽  
pp. 5424-5432 ◽  
Author(s):  
Maike Buchner ◽  
Simon Fuchs ◽  
Gabriele Prinz ◽  
Dietmar Pfeifer ◽  
Kilian Bartholomé ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
Therapeutic Target ◽  
Lymphocytic Leukemia ◽  
Spleen Tyrosine Kinase ◽  
Potential Therapeutic Target

scholarly journals Spleen Tyrosine Kinase Is Involved in the CD38 Signal Transduction Pathway in Chronic Lymphocytic Leukemia

PLoS ONE ◽  
2016 ◽  
Vol 11 (12) ◽  
pp. e0169159 ◽  
Author(s):  
Marco Benkisser-Petersen ◽  
Maike Buchner ◽  
Arlette Dörffel ◽  
Marcus Dühren-von-Minden ◽  
Rainer Claus ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
Signal Transduction Pathway ◽  
Lymphocytic Leukemia ◽  
Transduction Pathway ◽  
Spleen Tyrosine Kinase

scholarly journals A potential therapeutic strategy for chronic lymphocytic leukemia by combining Idelalisib and GS-9973, a novel spleen tyrosine kinase (Syk) inhibitor

Oncotarget ◽  
2014 ◽  
Vol 5 (4) ◽  
pp. 908-915 ◽  
Author(s):  
Russell T Burke ◽  
Sarah Meadows ◽  
Marc M Loriaux ◽  
Kevin S. Currie ◽  
Scott A. Mitchell ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
Therapeutic Strategy ◽  
Lymphocytic Leukemia ◽  
Spleen Tyrosine Kinase ◽  
Syk Inhibitor

scholarly journals Selective, novel spleen tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration

Leukemia ◽  
2012 ◽  
Vol 26 (7) ◽  
pp. 1576-1583 ◽  
Author(s):  
J Hoellenriegel ◽  
G P Coffey ◽  
U Sinha ◽  
A Pandey ◽  
M Sivina ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Activation ◽  
Lymphocytic Leukemia ◽  
B Cell Activation ◽  
Spleen Tyrosine Kinase ◽  
And Migration

scholarly journals Spleen Tyrosine Kinase Inhibition Modulates p53 Activity

2017 ◽  
Vol 10 ◽  
pp. 117906601773156 ◽  
Author(s):  
Mohammad Althubiti
Keyword(s):  
Tyrosine Kinase ◽  
Survival Rates ◽  
Lymphocytic Leukemia ◽  
Spleen Tyrosine Kinase ◽  
Ht1080 Cell ◽  
P53 Expression ◽  
Chemical Inhibitors ◽  
Dependent Mechanism

Spleen tyrosine kinase (SYK) is a cytoplasmic enzyme that promotes survival and proliferation of B cells. SYK inhibition has shown promising results in the treatment of arthritis and chronic lymphocytic leukemia (CLL). However, in other context, it has been shown that SYK overexpression in epithelial cancer cells induced senescence in p53-dependent mechanism, which underscored its antineoplastic activity in vitro. Here, we show that SYK was induced in response of DNA damage in parallel with p53 levels. In addition, using chemical inhibitors of SYK reduced p53 levels in HCT116 and HT1080 cell lines, which underlines the role of SYK inhibition on p53 activity. Furthermore, SYK inhibition modulated the cell growth, which resulted in a decreasing in cell death. Interestingly, SYK expression showed a positive prognosis in patients with solid tumors in correlations with their survival rates, as expected negative correlation was seen between SYK expression and survival rate of patients with CLL. In conclusion, these findings demonstrate that SYK inhibition modulates p53 expression and activity in HCT116 and HT1080 cells. Reconsidering using of SYK inhibitors in clinical setting in the future should be evaluated carefully in accordance with these findings to prevent the formation of secondary malignancies.

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