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

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.

• Authors: J Hoellenriegel, G P Coffey, U Sinha, A Pandey, M Sivina, A Ferrajoli, F Ravandi, W G Wierda, S O'Brien, M J Keating, J A Burger
• Journal: Leukemia (Leukemia) Vol. 26 Issue 7 Pg. 1576-83 (Jul 2012) ISSN: 1476-5551 [Electronic] England
• PMID: 22362000 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(2-aminocyclohexylamino)-4-(m-tolylamino)pyrimidine-5-carboxamide
• 4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-(2-aminocyclohexylamino)pyrimidine-5-carboxamide
• Cyclohexylamines
• Intracellular Signaling Peptides and Proteins
• Protein Kinase Inhibitors
• Pyrimidines
• Protein-Tyrosine Kinases
• SYK protein, human
• Syk Kinase

Topics

• 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, metabolism)
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, enzymology, pathology)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Pyrimidines (pharmacology)
• Stromal Cells (cytology, drug effects, metabolism)
• Syk Kinase
• Tumor Cells, Cultured