Reference - Detail
| RRC ID | 43687 |
|---|---|
| Author | Hoellenriegel J, Coffey GP, Sinha U, Pandey A, Sivina M, Ferrajoli A, Ravandi F, Wierda WG, O'Brien S, Keating MJ, Burger JA. |
| Title | Selective, novel spleen tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration. |
| Journal | Leukemia |
| Abstract |
Syk is a protein tyrosine kinase that couples B-cell receptor (BCR) activation with downstream signaling pathways, affecting cell survival and proliferation. Moreover, Syk is involved in BCR-independent functions, such as B-cell migration and adhesion. In chronic lymphocytic leukemia (CLL), Syk becomes activated by external signals from the tissue microenvironment, and was targeted in a first clinical trial with R788 (fostamatinib), a relatively nonspecific Syk inhibitor. Here, we characterize the activity of two novel, highly selective Syk inhibitors, PRT318 and P505-15, in assays that model CLL interactions with the microenvironment. PRT318 and P505-15 effectively antagonize CLL cell survival after BCR triggering and in nurse-like cell-co-cultures. Moreover, they inhibit BCR-dependent secretion of the chemokines CCL3 and CCL4 by CLL cells, and leukemia cell migration toward the tissue homing chemokines CXCL12, CXCL13, and beneath stromal cells. PRT318 and P505-15 furthermore inhibit Syk and extracellular signal-regulated kinase phosphorylation after BCR triggering. These findings demonstrate that the selective Syk inhibitors PRT318 and P505-15 are highly effective for inhibition of CLL survival and tissue homing circuits, and support the therapeutic development of these agents in patients with CLL, other B-cell malignancies and autoimmune disorders. |
| Volume | 26(7) |
| Pages | 1576-83 |
| Published | 2012-7-1 |
| DOI | 10.1038/leu.2012.24 |
| PII | leu201224 |
| PMID | 22362000 |
| PMC | PMC5459370 |
| MeSH | Apoptosis / drug effects Blotting, Western Cell Adhesion / drug effects Cell Movement / drug effects* Cell Proliferation / drug effects Chemotaxis Cyclohexylamines / pharmacology* Enzyme-Linked Immunosorbent Assay Flow Cytometry Humans Intracellular Signaling Peptides and Proteins / antagonists & inhibitors* Intracellular Signaling Peptides and Proteins / metabolism Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy* Leukemia, Lymphocytic, Chronic, B-Cell / enzymology Leukemia, Lymphocytic, Chronic, B-Cell / pathology* Phosphorylation / drug effects Protein Kinase Inhibitors / pharmacology* Protein-Tyrosine Kinases / antagonists & inhibitors* Protein-Tyrosine Kinases / metabolism Pyrimidines / pharmacology* Stromal Cells / cytology Stromal Cells / drug effects Stromal Cells / metabolism Syk Kinase Tumor Cells, Cultured |
| IF | 8.665 |
| Times Cited | 102 |
| WOS Category | ONCOLOGY HEMATOLOGY |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 2 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | KUSA-H1(RCB1990) 9-15C(RCB2323) TSt-4(RCB2116) |